13-alkylogona-1, 3, 5 (10), 9 (11)-tetraenes



July 2, 1968 G. A. HUGHES ET AL 3,391,170

Filed sept. 21, 1965 2 sheets-sheer 1 FIG. l H c\ (iN-120H CH2-Br CH2 CHCH I CH w30 Ca 2 cH3o Cfla 2 c1430 Ca 2 I II III W2 CH2 0 CH3 BIII H 2 o0 CH2 CH2 c|T42\N(c2H5)2 gl \mc2n5)2 Cx c` o o a @+2 cH cH cHso caso caa cHso Cz a EHI Y E C,CH=CH2 of, @L CH O f 2 3 CH2 CH3 m CIIHB ,HB cH cHcH 2 o 2 o z o CH3() CH30 cuo IX X XI |H5 CH2 o cnao XI XIII /N VEN TORSGORDON A. HUGHES HERCHEL SMITH July 2, 1968 s. A. HUGHES ET Al.3,391,170

Filed Sept. 21, 1965 2 Sheets-Sheet FIG. 3 CH CH CHBO C0430 XI XN Fla. 4CH3 CH3 I l CH2 0H CH2 OH "'CECH "'CHZCHB CH3@ CHSO Y XIII XI CH2 o cu2o O O O cuao cHao MII XII 9': EHS cu2 o CH2 o CH3() CHSO XI ,m

INVENTORS GORDON A. HUGHES HERCH L SMITH A 7 TORNE Y United StatesPatent O 3,391,170 lli-ALKYLGONA-LS,5(10),9(1DJIETRAENES Gordon AlanHughes, Wayne, Pa., and Herchel Smith,

500 Chestnut Lane, Wayne, Pa. 19087; said Hughes assignor to said SmithContinuation-impart of application Ser. No. 228,384,

Oct. 4, 1962. This application Sept. 21, 1965, Ser.

1.5 Claims. (Cl. 260-397.45)

ABSTRACT F THE DlSCLSURE The preparation of13methylgona-l,3,5(10),9(11)- tetraenes and novell3-polycarbon-alkylgona-1,3,5(10), 9(1l)tetraenes by rearrangement ofthe corresponding gona-1,3,5(l0),8tetraenes is described. Thesecompounds have estrogenic and anti-lipemic activity and, in addition,are useful as intermediates for the preparation of compounds havingestrogenic, anti-lipemic, progestational, anabolic, and androgenicactivities.

This application a continuation-in-part of co-pending appliaction Ser.No. 228,384, tiled Oct. 4, 1962; which in turn is a continuation ofapplications Ser. No. 57,904, filed Sept. 23, 1960; Ser. No. 91,341,filed Feb. 24, 1961; Ser. No. 137,535, filed Sept. l2, 1961; Ser. No.195,000, filed May l5, 1962; and Ser. No. 196,557, filed May 16,

1962; all abandoned.

This invention relates to compositions of matter classiied in the art ofchemistry as substituted unsaturatedgonane derivatives, to intermediatestherefor, and to processes for making and using such compositions.

In describing the invention, reference will `be made in the followingspecification to the annexed drawings, wherein:

FIGURE 1 illustrates schematically the reaction sequence for preparing aIS-alkylgona- 1,3,5(l0),9(11) tetraene, specifically13-ethyl-3-methoxygona-1,3,5(l0), 9( l 1)-tetraen-17-one.

,FIGURE 2 illustrates schematically the ethynylation of al3-alkylgona-l,3,5(10),9(ll)tetraen17one to prepare al3-alkylgona-1,3,5(10),9(11)tetraen17ol, specifically 13 ethyl 17aethynyl 3 methoxygona 1,3,5(10), 9(11)tetraen17-ol from 13,8-ethyl-3-rnethoxygona-1,3, 5(10),9(11)-tetraen-l7-one.

FIGURE 3 illustrates schematically the reduction of a13-alkylgona-l,3,5(10),9(11)-tetraen-17-one to prepare a13-alkylgona-l,3,5(10),9(11)-tetr'aen-17-ol, specifically 13p ethyl- 3methoxygona 1,3,5(10),9(11) tetraen- 17-ol from13-ethyl-3-methoxygona-1,3,5( 10) ,9 l l tetraen-l7-one.

FIGURE 4 illustrates schematically the selective hydrogenation of a13-alkyl-l7-ethynylgona-1,3,5(10),9(11) tetraene to prepare al3,17-diethylgona-l,3,5(10),9(11)- FIGURE 5 illustrates schematicallythe reaction sequence for preparing a 13-alkylgona-l,3,5(l0),9(l1)-tetraene from a 2alkyl-2-(6-phenyl-3-oxohexyl)-l,3-cyclopentane-l,3dione, specificallyl3-ethyl-3-methoxygona-l,3,5(10),9(11)-tetraen-17-one.

The invention sought to be patented, in a principal composition aspect,is described as residing inthe concept of a chemical compound having thegona-1,3,5(10),9- (11)-tetraene nucleus and having attached thereto inthe 13-position a monovalent polycarbon-alkyl radical.

The tangible embodiments of the composition aspect of the inventionpossess the inherent general physical properties of being Whitecrystalline solids, are substantially insoluble in Water and aregenerally soluble in polar 3,391,170 Patented July 2, 1968 ice solventssuch as dimethylacetamide. Examination of cornpounds produced accordingto the hereinafter described process reveals, upon ultraviolet andinfrared spectrographic analysis, spectral data supporting the molecularstructures herein set forth. The aforementioned physicalcharacteristics, taken together with the nature of the startingmaterials and the mode of synthesis, confirm the structure of thecompositions sought to be patented.

The tangible embodiments of the invention possess the inherent applieduse of characteristics of exerting qualitatively varying hormone effectsin animals as evidenced by pharmacological evaluation according tostandard test procedures. Such tangible embodiments show estrogenic andblood lipid lowering effects, and these ndings indicate their usefulnessin the treatment of female hypogonadism, amenorrhea, dysmenorrhea,ovulation block, functional uterine bleeding, acne, arteriosclerosis,osteoporosis, hormone dependent tumors, infertility, and incontraception. In particular, it has been established that alterationsof the natural steroid structure made possible by our discovery resultnot merely in a change of degree of hormonal activity but, as a resultof the separation of types of hormonal activity, alter in an unexpectedway its basic nature so that a desirable hormone eifect is maximized andan undesirable hormone elect is minimized.

In addition to their inherent applied use characteristics, theintermediate compositions of this invention are useful in practicing theprocess aspect of the present invention in the making of the principalgonane compositions of the invention according to the sequence ofreactions described herein.

The invention sought to be patented, in a principal process of makingthe compositions aspect, is described as residing in the concept of thesequence of reactions including: converting a compound having aS-phenyl-pent-l-yne nucleus, ring-unsubstituted in at least one positionortho to the point of chain attachment, lby means of a Mannich typereaction, to its acetylenic amine derivative; hydrating the acetyleniclinkage to form a S-keto compound; reacting such 3-keto substratecompound with a nucleophilic 2 monovalent alkyl 1,3 dioxocyclopentanocompound under Michael condensation conditions to attach thecyclopentano compound through its 2-position carbon atom to thel-position carbon atom of the 3-keto compound; treating the bicyclictriketone formed in the preceding step with an acidic `dehydrating agentthereby to effect a double cyclodehydration to form a1,3,5(l0),8,l4-pentadehydro-lB-alkylgonane, and thereafter selectivelysaturating the 14( 15) double bond of said gonane with hydrogen in thepresence of a catalyst and isomerizing the 8(9) double bond of theproduct under acidic conditions.

The invention sought to be patented in a sub-generic composition aspectis described as residing in the concept of a13-alkylgona1,3,5(10),9(11)-tetraen17ol (FIG- URE 3, XIV), of which aspecific embodiment in which the alkyl group is l3-ethyl is hereinafterdescribed.

The tangible embodiments of said sub-generic composition aspect possessthe use characteristic of varying hormone effects in animals, asevidenced by pharmacological evaluation by standard test procedures, andin particular in certain instances anti-atherogenic effects accompaniedby unexpected separation of activities.

The invention sought to be patented in a second process aspect isdescribed as residing in the concept of alkynylating a compound having agona-l,3,5(l0),9(1l)-tetraen 17-one nucleus (FIGURE 2, XI) and obtainingthe corresponding 17a-alkynylgona-1,3,5(10),9(11)-tetraen-l7-ol (FIGURE2, XIII).

The invention sought to be patented in a third process aspect isdescribed as residing in the concept of selectively hydrogenating in thepresence of a catalyst a 17a-alkynylgona-l,3,5(l0),9(l1)-tetraen-l7-ol(FIGURE 4, Xlll) 3 to obtain al7a-alkylgona-l,3,5(l0),9(l1)-tetraen-17-ol (FIGURE 4, XV).

The invention sought to be patented in a fourth process aspect, asillustrated in annexed FIGURE 5, is described as residing in the conceptof a sequence of reactions to form the gonane structure with the naturalconfiguration of hydrogen atoms at the 8 and 14-positions including:treating the bicyclic ketone formed in the Michael reaction of a S-ketosubstrate compound with a nueleophilic 1,3-dioxocyclopentano compoundhaving at least one hydrogen at the 2-position (VIII) under aldolcondensation conditions, i.e., in the presence of a basic catalyst, andif a suitable activating substituent is not present on the aromaticring, in the presence of an acid catalyst, to form the tricyclicdiketone (XVI): reducing the C-ring unsaturation to form Compound XVII(by whatever mechanism the hydrogen at the S-position is introduced, itcan on treatment with an acid or base take up the most stableconfiguration, i.e., the position trans to the other newly introducedhydrogen, by equilibrating through keto-enol tautomerism with theadjacent keto; thus when the first is a, having been introduced trans tothe 13-substituent by stereospecic means, the 8-carbon will be so thatthe natural configuration results) and closing the B-ring under acidicconditions at low temperature to form cornpound XI.

The manner of making the chemical compounds which are the startingmaterials for use in making the compounds of the invention, and for usein the processes of making the invention, are illustrated in copendingapplication Ser. No. 228,384 tiled Oct. 4, 1952.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same, as follows:

Referring now to FIGURE l7 wherein the compounds are assigned Romannumerals for identification schematically, the sequence of reactionsinvolved in the synthesis of a specific embodiment, namely,l3-ethy1-3-methoxygonol,3,5(l0),9(l1)-tetraen-17-one, is illustrated.3-(m- Methoxyphenyl)propanol (I) is heated with phosphorus tribrornidein benzene after dropwise addition in the cold to form3-(m-methoxyphenyl)-propyl bromide (II). This halogen compound (II)dissolved in tetrahydrofuran is condensed with sodium acetylide inliquid ammonia to obtain S-(m-methoxyphenyl)-l-pentyne (III). CompoundIII is allowed to stand under nitrogen with water, 30% formalin, aceticacid, diethylamine, dioxan, and cuprous chloride at 70 C. for about 12hours, whereby there is obtained 1diethylamino-6-(ni-methoxyphenyl)-Z-hexyne (IV), which is in turnhydrated in the presence of a mercury salt and sulfuric acid to forml-diethyl-amino-6- (m-methoxyphenyl)-3-hexanone (V). The ketamine (V)may eliminate diethylamine on distillation to give the vinyl ketone6-(m-methoxyphenyl)-l-hexen-3-one (VI). Either the ketamine (V) or theketone (VI), or mixtures thereof, is then reacted with2-ethyl-1,3-cyclopentanedione (VII) under Michael condensationconditions, eg., retluxing in methanolic potassium hydroxide to form2-ethyl-2-[6-(mmethoxyphenyl) 3 oxohexyl] 1,3-cyclopentanedione (VIII).

Compound VIII is then cyclodehydrated at the rel'lux temperature of asolvent, such as benzene, in the presence of a dehydrating acid, such asp-toluene sultonic acid, to effect simultaneous ring closures to givethe tetracyclic compound 13 ethyl 3-methoxygonal,3,5(l0),8,14pentane-l7-one (IX). The 14-unsaturation of Compound IX is thenselectively hydrogenated in the presence of a metal catalyst, such as 2%palladized calcium carbonate, to form13ticthyl3methoxygonal,3,5(lO),8-tetraen-l7- ane (X). Compound (X) isthen isomerized by treating with a strong acid such as hydrochloric orp-toluenesulfonie acid to form l3,6-cthyl-3-methoxygona-1,3,5(10),9(ll)tetraenl7-one (XI).

Referring now to FIGURE 2 wherein the compounds are assigned Romannumerals for identification schematically, a specific embodiment of theinvention, 13,3- ethyl 17aethynyl-3-methoxygona-1,3,5(10),9(11)-tetraen-l7-ol (XIII) is formed byethynylating l3-ethyl- 3 methoxygona-1,3,5(10),9(11)-tetraen-l7-one withan alkali metal acetylide or an acetylenic Grignard reagent.

Referring now to FIGURE 4, another specic embodiment of the invention,l3,17-diethyl-3-methoxygona- 1,3,5(10),9(11)-tetraen-17-ol (XV) isformed by selectively hydrogenating in the presence of a metal catalystl3-ethyl-l7a-ethynyl-3-methoxygona 1,3,5(l0),9(1l) tetraen-l7-ol (XIII)until the acetylenic group is Saturated with hydrogen.

Referring now to FIGURE 5, wherein the compounds are assigned Romannumerals for identification schematically, the sequence of reactionsinvolved in an alternate process for cyclizing the2-alkyl2(6-phenyl-3oxohexyl) 1,3-cyclopentanedione to obtain thetetracyclic 13-alkylgona-l,3,5(10),9(l1)-tetraene is illustrated.Internal aldol condensation and dehydration of2-ethyl-2-[6-m-methoxyphenyl)-3-oxohexyl]-l,3-cyclopentanedione (VIII)forms 8 etl1yl-5,6,7,8-tetrahydro-4-m-methoxyphenethylindane- 1,5-dione.The newly formed unsaturation of Compound XVI is hydrogenated to form 8ethylhexahydro 4-mmethoxyphenethylindane-1,5-dione (XVII). B-ringclosure of Compound XVII proceeds at room temperature under acidconditions to form l3f2-ethyl-3rnethoxygona-l,3,5(l0),9(1l)-tetraen17-one (XI).

While the hereinbefore described processes produce novel andsteroidal-like compounds which have an unnatural substituent at the11i-position, it is apparent that the novel and valuable processes ofthe invention offer a unique feasible route to the corresponding naturalsteroids if the nucleophilic compound used in the Michael condensationstep is Z-methyl-1,3-cyclopentanedione.

The aromatic ring of the phenylpropanol (FIGURE l, I) used as thestarting material for the preparation of the compositions and initialpreparations of the invention may have one or more substituents,provided, however, at least one position ortho to the position ofpropanol-chain attachment is unsubstituted so that cyclodehydration toform a cyclic structure can eventually be electuated. To activate suchortho position for said subsequent ring closure, a para-directing group(referring to electrophilic aromatic substitution) such as hydroxy,acyloxy, alkoxy, amino, alkylamino, or acylamino is a necessarysubstituent on the aromatic ring. The group may be present initially ormay be introduced later but before ring closure, either directly, or byconversion from a meta-directing group such as nitro. The termpara-directing group (referring to electrophilic aromatic substitution)as used herein means an activating group such as those hereinbeforelisted and which activates all positions on the aromatic nucleus. Thus,if the group is para-directing, as defined above, it can `be in aposition meta to the ortho position to which ring closure is limited bysteric considerations, said position being activated even though anotherposition is more highly activated. Ring closure could not occur at thesaid more highly activated position because of the above-mentionedsteric limitations. For the processes of the invention and except forthe limitations expressed in this specilication, variations of thesubstituents on the A-ring of the fully formed tetracyctic structures,or the intermediates leading thereto, are full equivalents of eachother. After the tetracyclic structure has been formed, substituents canbe introduced into the aromatic A-ring which are not limited as above;however, ir" such Substituted compound is to undergo a reduction, thegroup is preferably one not sensitive to reduction. For the processes ofthe invention and except` for the limitations expressed in thisspecification, variations of the substituents on the A-ring of the fullyformed tetracyclic structures, or on the intermediates leading thereto,are full equivalents of each other.

The carbon atom to which the phenyl group of the starting propanol (I)is attached can be substituted, as, for example, with an alkyl group,such as methyl or ethyl. This atom will appear in the tetracyclicstructures of the invention in the -position.

When the nucleophilic compound is 2methyll,3cyclo pentenedione, theinvention provides a unique total synthesis for natural steroids: thehydrogens at the 8-position, 9-position, and lll-position being a, anda, respectively, as in the natural steroids. Thus such valuabletherapeutic substances as estrone, estradiol, and 19nortestosterone aremade available from easily obtainable and relatively simple andinexpensive starting materials.

Moreover, by varying the group at the Z-position of the nucleophilicMichael condensation reactant, the invention provides a way to producecompounds resembling the natural steroids save at the l3-position.

The starting materials for the preparation of the 2-substituted1,3-cyclopentanediones are ketones of the structure RCH2COCH3, where Ris the substituent which will appear at the 2-position of the1,3-cyclopentanediones. The starting ketone is reacted with diethyloxalate in the presence of base to form a cyclopentane-l,3,4-trione-5-glyoxylic ester substituted at position 2 with the group R present inthe starting ketone. The product is treated with acid to remove the5-substituent, and the 4-ketone function is then removed by Wolt-Kishnerreduction, involving selective semicarbazone formation at C4 and heatingthe product with base such as sodium hydroxide. On acidification therequired 2substituted1,3-cyclopentane dione can be isolated. Thus, thegroup R, which eventually forms the 2substituent of the 1,3cyclopentanedione, can be any organic group which is stable to acid and to Wolff-Kishner condition and can be methyl, ethyl, propyl, cetyl.ldiethylaminoethyl, etc. Thus, by varying the substituent at the2-position of the 1,3-cyclopentanedione, alkyl groups of varying chainlength such as, for example, ethyl, isopropyl, cetyl, etc., may beintroduced to form the gonane correspondingly substituted at thel3-position.

The 2-carbon atom of the starting phenyl-propanol (I) can also besubstituted, as, for example, with an alkyl group, such as methyl andethyl, and7 as such, be unchanged throughout the subsequent synthesis,In the tetracyclic structures of the invention this carbon atom willappear in the 7-position.

For the processes of the invention and except for the limitationsexpressed in this spe-cication, variations ot the B-ring on the fullyformed tetracyclic structures, or on the intermediates leading thereto,are full equivalents of each other.

In the Michael reaction step, the 3-keto substrate compound can ybe a6phenyl-l-hexen3-one, or alternatively, a 6-phenyl-3-hexanone havingattached to the l-position a group which will eliminate with hydrogen toform a 6-phenyl-lhexen3-one under Michael conditions. Thus, a 3-ketocompound with a l-dialkylamino substituent or its quaternary salt, a1-halo substituent, or a l-hydroxy substituent will react with thenucleophilic compound to the Michael product. The nucleophilic compoundcan be a carbocyclic-1,3-dione of varying ring size, as for ex ample, ave-membered ring, a six-membered ring, etc., ultimately forming acorresponding live-membered, a sixmembered, etc., D-ring in thetetracyclic structure. The 1,3-cyclodione may also contain a hetero atomat positions other than position 2, thereby to provide a heterocyclicD-ring in the tetracyclic structure. Aeylic nucleophilic compounds canbe used in conducting the Michael reaction step and the openchain of theresulting product there* after ringeclosed to form a cyclic D-ring.

For the processes of the invention, and except for the limitationsexpressed in this specification, variations of the D-ring on the fullyformed tetracyclic structure, or on the intermediates leading thereto,are full equivalents oi: each other. Further, gonanes may be preparedwherein the l3-position is substituted with any organic radical. Thus,but without limiting the generality of the foregoing,

an aralkyl, cycloalkylalkyl, or a polycarbon-alkylene bridge bearing ahydr0xy, amino, or :alkylamino, substituent can readily be placed in thel3-position, and from such compounds other variations of the l3-positionsubstituent can be prepared, as haloalkyls tirom hydroxyalkyls, orquaternary salts, amides, alkenyls, etc. from aminoalkyls.

For the processes of the invention and except for the limitationsexpressed in this specification, variations at the l3-position of thefully formed tetracyclic structures or on the intermediates leadingthereto are the full equivalents of the claimed l3-positionpolycarbon-alkyl substituents, having physiological activity of the sametype.

In any of the intermediate structures or in the tetracyclic structuresof the invention wherein the 17-position, or position correspondingthereto in the gonane nucleus, is carbonyl, the carbonyl group can beconverted to a group such as hydroxymethylene by lithium aluminumhydride reduction; to acyloxymethylene by esterication of thehydroxymethylene group so formed; to alkoxymethylene by etherication ofthe hydroxymethylene group; to alkyl hydroxymethylene by addition of theappropriate organometallic reagent to the carbonyl; or toalkynylhydroxymethylene by addition of the appropriate alkali metal f'acetylide in a suitable insert solvent; all in the known manners. Thecarbonyl group may also be ketalized or thioketalized by treating withthe appropriate alcohol or glycol, in a suitable solvent under acidicconditions, as in the presence of an acid such as sulfuric acid,p-toluene acid, or boron trifluoride etherate, with heating wherenecessary, according to the known art.

The specic reactions involved in the processes of the invention will nowbe considered, as follows, reference being made to the drawings fortypifying compounds:

The vinyl ketones (VI) are prepared by elimination of dialkylamine fromthe corresponding dialkylaminoethyl aminoketones (V), obtained byhydration of the acetylenic linkage in an acetylenic amine (IV). Theacetylenic amines (IV) can be themselves prepared by a Mannich reactionfrom the corresponding acetylene (III) with formaldehyde and adialkylamine. The hydration can be carried out, for example, in aqueoussulfuric acid with mercuric sulfate as a catalyst. The correspondingquaternary salts, which may also be used in the subsequent Michaelcondensation, can be obtained by quaternization of the correspondingacetylenic dialkylaminoethyl amine, followed by hydration, or byquaternization of the corresponding acetylenic dialkylaminoethyl amine,followed by hydration, or by quaternization of the ketoamine. The vinylketones can be prepared from these derivatives by the above eliminationreaction. Thus the ketoamine or its quaternary salt can be treated witha base for this purpose, forexample, with sodium hydroxide or a sodiumalkoxide.

The vinyl ketones (VI) and dialkylamino ketones (V) are condensed with anucleophilic compound under Michael reaction conditions. Thus thecondensation can be carried out [by bringing the two reagents togetherin solution in the presence of a base, for example, pyridine,triethylamine, diethylamine, sodium hydroxide, or sodium methoxide, andheating as required. The nature and amount of base employed in thecondensation reaction will depend upon the particular reagents used.Where the vinyl ketone derivative employed is a keto-amine anddisalkylamine is eliminated in the reaction, no added base may berequired. Where the compound is a 2-alkylcyclopentane-1,3-dione (VII),the compound to be condensed with it is preferably a vinyl ketone, andthe dione is used in excess of the molecular equivalent quantity.Suitable solvents are hydrocarbons, such as benzene, and anhydrousalcohols, such as methanol. If the reaction is carried out in benzeneunder refluxing conditions, water formed in the condensation may beazcotroped out of the reaction mixture with a Dean-Stark type trap.

As hcreinbetore noted, monocyclodehydration of the C-ring isaccomplished by an internal aldol condensation. The cyclodehydration cantherefore be carried out using conditions generally applicable for analdol condensation, i.e., in the presence of an acid or basic catalystsuch as NaOH, p-toluene sulfonic acid, triethylamine ibenzoate, aluminumtertiary butoxide, and the like, either at room temperature oraccompanied by heating if necessary. In most instances, we prefer tocarry out the cyclic dehydration at the boiling point of the solvent topermit azeotropic removal of the water formed during the course of thereaction, inasmuch as the aldol reaction is a reversible one. Preferredas solvents are the low boiling anhydrous aromatic hydrocarbons, such asbenzene and xylene C-ring closure occurs regardless of the nature of thesubstitution on the aromatic ring.

The Deduction of the 8(14) unsaturation in the tricyclic compounds iscarried out by catalytic hydrogenation either at room temperature orabove. It is found that when hydrogen and a palladium-on-charcoalcatalyst are used, the hydrogen introduced at the carbon lll-position isprincipally in the configuration trans to the group attached at thel3-position. By whatever mechanism the hydrogen at the S-position isintroduced, it can on treatment with an acid or base take up the moststable configuration, i.e., the position trans to the other newlyintroduced hydrogen, by equilibrating through keto-enol tautomerism withthe adjacent keto group. Thus the second hydrogen atom can be made totake up the -configuration when the rst is a.

The configuration of the hydrogen atom introduced by palladiumhydrogenation at the l4-carbon has been independently proved by reducingthe keto group of Compound XVIII.

V MCO- id at the 17a-position (steroid enumeration) using sodiumborohydride, a method selective for that position while leaving theother keto group untouched, and then reducing the resulting keto-alcohol(XIX) XVIII ANO@ XIX MCO

/\I Dit@ which is converted by methanolic hydrochloric acid MeO , to thetetracyclic ketone (XXII), identical to that prepared by thehydrogenation of the l 1,1 l 0^@ Meo XXII 8,14 double bond compoundXVIII followed by acid cyclodehydration, whose structure was determinedby reduction of the 9(11) double bond and conversion to the knownbenzylidene derivative.

The B-ring closure is brought about under acidic conditions. Suitableare strong acids such as sulfuric, hydrochloric, p-toluene sulfonic,etc. in solvents such as benzene, toluene, anhydrous alcohol, etc. Thereaction is generally carried out at room temperature or below sinceheat may promote the formation of an aromatic B-ring. The preferredtreatment is with methanolic hydrochloric acid at room temperature. Ashereinbefore noted, it has been found that the ease of B-ring closure ofthe compounds of the invention to form tetracyclic compounds is affectedby the nature of the substituent present on the preformed aromaticA-ring, and that subsequent cyclization is easier to carry out when thepreformed aromatic A-ring contains a substituent which activates theposition at which cyclization is to occur.

Where a compound is to be used directly for B-ring closure, it will inpractice be one containing such a substituent. Those substituents whichcause subsequent B- ring closure to occur readily are substituents parato the position of ring closure which are groups that in electrophilicaromatic substitution activate an aromatic ring and are predominantlyoand p-directing; for example, the hydroxy or alkoxy group.

The double cyclodehydration is brought about by dissolving a compoundtypified by Compound VIII in benzene containing a catalytic amount ofp-toluene sulfonic acid and boiling the mixture under a Dean-Stark trapuntil two equivalents of water have been collected, or alternatively, bytreating the same triketone with polyphosphoric acid at room temperatureor slightly above until ring closure is complete.

The selective hydrogenation of the gona1,3,5(10),8, 14pentaenes typifiedby Compound IX is carried out by means of 2% palladized calciumcarbonate. As hereinbefore noted, suprisingly, the catalytichydrogenation results in addition of hydrogen to the llt-double bond insuch a way as to give the natural stereochemical configuration; that is,the hydrogen adds at 14-trans to the alkyl at 13. Selective reduction ofthe 14-ethylenic linkage is achieved by use of catalyst-solventcombination which shows adequate selectivity, and stopping thehydrogenation when the theoretical amount of hydrogen has reacted.Solvents showing selectivity in this regard are the nonprotonicsolvents, that is, hydrocarbons and ethers; benzene, toluene, naphtha,dioxan, dibutyl ether, and diethyl ether are examples of suitablenonprotonic solvents. On

the other hand, protonic solvents such as acetic acid and ethanol appearto be largely non-selective.

It has been found that a moderately active Raney nickel catalystprovides good selectivity in a suitable solvent. If a Raney nickelcatalyst of low activity is employed, the hydrogenation may be too slowto be useful; on the other hand, a vigorous catalyst shows poorselectivity, and some saturation of the 8,9-ethylenic bond may occursimultaneously with the hydrogenation at the 14,15-position.

If desired, other moderately active hydrogenation catalysts may be usedinstead of Raney nickel; for example, palladium on barium sulfate or onalkaline earth metal carbonate or on charcoal have all been foundsuitable in this selective hydrogenation.

Isomerization of the 8(9) bond of the gona-1,3,5(10), S-tetraenes to the9(11 )position is brought about by treating a solution of the compoundin a solvent with a strong acid, with heating as required. Thushydrochloric acid in ethanol or p-toluenesulfonic acid in benzene aresuitable systems to effect isomerization.

While the tetracyclic compounds in this specification and the appendedexamples are named to describe the configuration corresponding to thatof the natural steroids, it is to be understood that unless otherwiseindicated, the product of each of the given manipulative procedures is aracemic mixture which contains said named compound and its enantiomorph.

Representative formulations embodying specific compositions of thisinvention follow:

A pharmaceutical tablet for use as an oral antiatherogenic agentconsists of the following ingredients:

Mg. 3-benzyloxy-13ethylgona1,3,5( 10),9(11 tetraen- 17e-ol A capsule foruse as an oral anti-atherogenic agentcontains, in encapsulating gelatin,the following ingredients:

Finely divided silica lubricant Magnesium stearate powder 5 Powderedcorn starch 113 Lactose powder, q.s.

Pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, dispersible granules,capsules, cachets, and suppositories. A solid carrier can be one or moresubstances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, ortablet-disintegrating agents: it can also be an encapsulating material.ln powders the carrier is a finely divided compound. In the tablets thecompound is mixed with carrier having the necessary binding propertiesin suitable proportions and compacted in the shape and size desired. Thepowders and tablets, preferably contain from 5 or 10 to 99% of theactive ingredient. Suitable solid carriers are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methyl cellulose, sodium carboxymethylcellulose, alow melting wax, and cocoa butter. The term preparation is intended toinclude the formulation of the compound with encapsulating material ascarrier providing a capsule in which the compound (with or without othercarriers) is surrounded by carrier, which is thus in association withit.

Similarly, cachets are included. Tablets, powders, cachets, and capsulescan be used for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions.The compounds are insoluble in water, but can be dissolved inaqueous-organic solvent mixtures that are non-toxic in the amounts used.As an example may be mentioned water-propylene glycol solutions forparenteral injection. Liquid preparations can also be formulated insolution in aqueous polyethylene glycol solutions. Aqueous suspensionsuitable for oral use can be made by dispensing the finely dividedcompound in vwater with viscous material, natural or synthetic gums,resins, etc., for example, gum arabic, ion-exchange resins,methylcellulose, sodium carboxymethylecllulose and other well-knownsuspending agents.

Preferably the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is sub-divided in unit doses containingappropriate quantities of the compound: the unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, for example, packeted powders of vials or ampules. The unitdosage form can be a capsule, cachet, or tablet itself, or it can be theappropriate number of any of these in packaged form. The quantity ofcompound in a unit dose of preparation may be varied or adjusted from 1mg. to mg. (generally within the range of 2.5 to 25 mg.) according tothe particular application and the potency of the active ingredient.

The claimed compositions having physiological activity can beincorporated into pharmaceutical formulations includingsustained-release agents.

The following preparations illustrate the manner of making the chemicalcompounds which are'the starting materials for use in the processes ofthe invention.

Preparation 1.-3- 3 -methoxyphenyD -n-propyl bromide Cool3-(3-methoxyphenyl)propan-l-ol (125 g.) in benzene (200 cc.) to 0 andadd a solution of phosphorus tribromide (86 g.) in benzene (150 cc.)dropwise so that the temperature of the mixture does not rise above 5.Keep the mixture at 0 for 1 hour and then heat at 60 for 3 hours. Cool,pour onto ice, dilute with ether and separate the organic layer. Washthe organic solution with 3 N aqueous sodium hydroxide, water and dry.Remove the solvent and distil the residue to obtain the title compound(131 g.), B.P. 146-148/17 mm. 11,318 1.5497.

C10H13Br, calculated: C, 52.4%; H, 5.7%; B1', 34.8%. Found: C, 54.4%; H,5.7%; Br, 34.7%.

Add 3(3-methoxyphenyl)-n-propyl bromide (14 g.) in tetrahydrofuran (15cc.) with rapid stirring to a solution of sodium acetylide (from 1.84 g.sodium) in liquid ammonia cc.) in a Dewar ask. Continue stirring for 22hours, then add ammonium chloride (3 g.) and water (50 cc.). `Collectthe product with ether and wash and dry the ethereal solution. Distil toobtain 5mmeth oxyphenylpent-l-yne (7.1 gr., 66% B.P. 75-78 C./0.06 mm.Hg.

CmHMO, calculated: C, 82.7%; H, 8.1%. Found: C, 82.2%; H, 7.8%.

Preparation 3.-l-diethylamino--m-methoxyphenylheX-Z-yne Allow5mmethoxyphenylpentl-yne (8 g.) to stand for 21 hours at 70 C. undernitrogen with water (21.5 cc.7, trioxan (0.5 g.), 30% formalin (5.5 g.),diethylamine (4 g.), acetic acid (2.75 g.), dioxan (25 cc.) and cuprouschloride (0.13 g.). Make the cooled solution alkaline with 10% aqueoussodium hydroxide and extract with ether; then extract the ether extractwith 10% hydrochloric acid; wash the acid extract with ether, basify andextract with ether, and then wash and dry the ether extract. Distil toobtain 1-diethylamino-G-m-methoxyphenyl-heX-2-yne (10.6 g., 885), B.P.l30-13l C./0.1 mm.

ll ClHgEN, calculated: C, 78.7%; H, 9.7%. Found: C, 78.9%; H, 9.6%.

Preparation 4.-l-diethylamino--m-methoxyphenylhexan-S-one and-m-methoxyphenylhex-1-en-3-one Add mercuric sulphate (0.45 g.) to aswirled solution of 1-diethylamino--m-methoxyphenylhex-Z-yne (8.5 g.) inconcentrated sulphuric acid (2.5 cc.) and water (25 ce). Keep thesolution under nitrogen at 75 C. for 1 hour, then cool, make basic with10% aqueous sodium hvdroxide, and tilter through `glass wool to removemercuric oxide. Extract product with ether and wash and dry the etherealsolution. Remove the solvent to obtain the crude ketoamine1-diethylamino-6-mmethoxyphenyl hexan-3-one, infrared absorption peak at1710111.. Distil under reduced pressure with partial elimination ofdiethylamine, to obtain a mixture of the ketoaminel-diethylamino-6-m-methoxyphenylhexan 3 one and the vinyl ketone 6 mmethoxyphenylhex-l-en-3-one (7.1 g., ca. 76%), B.P. 14C-145 C./0.1 mm.;infrared absorption peaks at 5.85 and 5.95 u, the ketoaminepredominating.

Rellux a mixture (5.25 g.) of 1-diethyiamino--m-methxyphenylhexan-3-oneand -m-methoxyphenylhex-1en 3-one with Z-ethylcyclopentane-1,3-dione(3.3 g.) in dry 0.12% methanolic solution oi potassium hydroxide for 18hours. Filter the resulting solution, evaporate to dryness and dissolvein the residue in ether. Wash the ether solution with alkali,hydrochloric acid, and water, dry and evaporate to obtain as residue thetriketone 2-(6-m-methoxyphenyl-3-oxohexyl)-2-ethylcyclopentane 1,3 dione(7.1 g.) as a gum.

Reiiux the triketone 2 ethyl-2-(6-mfmethoxyphenyl-3-oxo-hexyl)cyclopentane-l,3-dione (7.1 gn), in benzene (150 cc.) andtoluene-p-sulphonic acid (2 g.) until the theoretical amount of water(0.72 cc.) for double cyclodehydration has been collected in aDean-Stark separator. Wash the cooled reaction mixture after removal ofsolvent Linder reduced pressure, Bi. ca. 220/0.01 mm., to obtain analmost colorless glass (5.7 gn). Crystallize the glass from methanolcontaining a little ethyl acetate to obtain pure l3-ethyl-3 -methoxygona1,3,5(l0),8,14 pentaen17one (3.7 g), M.P. 77-80; ultraviolet absorptionpeak at 311 ma (e 28,000).

Omi-12202, calculated: C, 81.6%; H, 7.5%. Pound: C, 81.3%; H, 7.3%.

The following examples illustrate the manner of using the claimedprocesses of the invention for the preparation of the claimedcompositions of the invention.

To 135 methyl-3-methoxy-D-homogona-1,3,5(l0),8, 14-pentane-l7a-one (0.3g.) in dioxan (20 cc.) add a moderately active Raney nickel catalyst(ca. 0.2 g.). Hydrogenate at room temperature and atmospheric pressureuntil 2.4 cc. hydrogen has been absorbed. Filter off the catalyst andevaporate the filtrate to obtain a solid; recrystaliize from a mixtureof ethanol and ethyl acetate to obtain the title product (0.15 g), M.P.1Z0-150 C. Ultraviolet absorption peak at 275 ma (e 14,000).

This compound has estrogenic activity, lowers the lood lipid level, andis useful as an intermediate for preparing the `iormonal compounds ofthis invention.

Example 2.-13,8-methyl-3-methoxygona-1,3,5 10) S-tetraen-17-one Dissolve13(3methyl-3 methoxygona 1,3,5(10),8,14 pentaen-l7-one (l g.) in dioxan(33 cc.). To the solution and Raney nickel catalyst (ca. 0,5 g.) whichhas been prepared by the method of Pavlic and Adkins, l.

Amer. Chem. Soc., 1946, 68, 1471 and allow to stand for 24 hours.Hydrogenate at room temperature and pressure until the theoretical.amount of hydrogen (92 ce.) for saturation of one ethylenic linkage hasbeen absorbed. Towards the end of this period (5 hours) the rate ofhydrogenation drops markedly. Evaporate the solvent after removal ofcatalyst to obtain a gum which readily crystallizes. Recrystallize oncefrom ethanol to obtain the crude title product (0.69 g.), M.P. -l20;ultraviolet absorption peak at 278 mp (e 14,700).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 3.-l3-rnethyl-3-methoxygona-1,3,5 (10) ,8-tetraen-l7-oue Shake1312 methyl 3 methoxygona-1,3,5(10),8,14- pentaen-17-one (l g.) inbenzene (35 ce.) with a 10% palladium on barium sulphate catalyst (0.3g.) in the presence of hydrogen at atmospheric pressure until 90 cc.hydrogen has been absorbed. By the end of this period (ll/2 hours) therate of hydrogenation will have slowed down. Filter the mixture andevaporate the solvent to obtain n gum which solidiiies; recrystallizefrom ethanol to obtain the title product (0.68 g.), M.P. 11G-120;ultraviolet absorption peak at 278 mu (e 13,200).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Shake 13,6-ethyl-3-methoxy-D-hornogona 1,3.5(10),8, 14pentaen17aone(1.175 g.) in tetrahydrofuran (100 cc.) with 2% palladium on calciumcarbonate (0.5 g., prereduced) in an atmosphere of hydrogen until onemolecular equivalent of hydrogen has been absorbed. Filter the catalyst;evaporate the solvent, recrystallize the residue from ethanol to obtainthe title product (0.925 g), M.P. 104-107; ultraviolet absorption peakat 278 mu (e 15,680).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Dissolve 13p ethyl 3-methoxygona-1,3,5(10),8,14 pentaen-17-one (2 g.) indioxan (50 cc.) containing Raney nickel (ca. 0.5 g.) of moderate`activity and shake with hydrogen until cc., the amount corresponding toone molecular proportion has been absorbed. Recrystallize the isolatedproduct from methanol to obtain the title product (1.2 g.), M.P.11G-125; ultraviolet absorption peak at 280 ma (e 13,200).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 6 13/8-propyl-3-methoxygono-1,3,5(10),8 tetraen-17-one Condense2-propyl-1,3-cyclopentanedione (13.1 g.) in 0.12% methanolic potassiumhydroxide solution (90 cc.) with 6-mmethoxyphenylhex1-en-3-one (19.0g.), to obtain crude 2 propyl2(6-m-methoxyphenyl-3-oxohexyl)cyclopentane1,3dione (25.5 g.). Submit this Michael condensation product(23.4 g.) to double cyclodehydration; distil the product -at 200/ 10H1mm. and crystallize the distillate from ethanol, to obtain thetetracyclic diene ketone, M.P. 82-84; ultraviolet absorption peak at 310ma (e 24,700).

Selectively hydrogenate the diene ketone (5 g.) in benzene solution witha palladium on calcium carbonate catalyst until sufficient hydrogen hasbeen taken up to saturate the 14,15-ethylenic bond. Isolate the product(3.5 g.) as pink crystals from methanol, M.P. 11i-113.

13 This compound has estrogenic activity, lowers the blood lipid leveland is useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 7,-13 -isopropyl-3-methoxygona-1,3,5 l0 ,8- tetraen-17-onekShake -13 isopropyl 3 methoxygona-1,3,5(10),8, 14-pentaen-l7-one (2 g.)in dioxan (50 cc.) with a freshly prepared but moderately active Raneynickel catalyst (ca. 0.5 g.) in hydrogen at atmospheric pressure. When,after several hours the theoretical amount of hydrogen forhalf-hydrogenation (160 cc.) has been absorbed, ilter off the nickelcatalyst and remove the solvent by evaporation. Crystallize the residualgum from methanol to obtain the title product (1.2 g.), M.P. 85- l C.;ultraviolet absorption peak at 280 ma (e 11,800).

This compound has estrogenic activity, lowers the blood lipid level andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 8.-13-butyl-3-methoxygona-1,3,5 (10),8 tetraenl7one Condense 2butyl-1,3-cyclopentanedione (2.8 g.) in 0.12% methanolic potassiumhydroxidesolution (8 cc.) with 6-m-methoxyphenyl-hex-l-en-3-one (5 g.)by heating the mixture at 80 for 10 hours. Evaporate the solvent underreduced pressure and heat the residue with toluene p-sulphonic acid (2g.) in benzene (50 cc.) for 45 minutes using a Dean-Stark trap, toeffect double cyclodehydration. Add ether to the cooled reaction mixtureand evaporate the Washed and dried ether solution; recrystallize theresidue from ethanol to obtain the tetracyclic diene (1.9 g.), (M.P.53-55; ultraviolet absorption peak at 312 mp. (e 29,200).

Shake this tetracyclic diene (1.38 g.) in benzene (45 cc.) in hydrogenlat atmospheric pressure with a previously reduced 2% palladium oncalcium carbonate catalyst (0.5 g.). When 10'0 cc. hydrogen has beenabsorbed, discontinue the hydrogenation and lter ot the catalyst.Evaporate solvent and recrystallize the residue from methanol to obtainthe title product (1.02 g.')., M.P. 10i-108; ultraviolet absorption peakat 278 ma (e 16,700).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 9.-13-isobutyl-S-methoxygona-1,3,5(1(1),8-

tetraen-17-one To a pre-reduced suspension of 2% pall-adium on calciumcarbonate catalyst (7.0 g.) in benzene (30 cc.) add a solution of 13,8isobutyl-S-methoxygona-1,3,5(10), 8,14-pentaen-17-one (20.0 g.) inbenzene (500 cc.) and hydrogenate the mixture at atmospheric pressureuntil one mole equivalent of hydrogen is consumed. After the catalyst isremoved by ltration, evaporate the solvent to obtain a gum which oncrystallization from ethanol affords the title product (17.1 g.; 71%), MP. 1l7119; ultraviolet absorption peak at 278 ma (e 14,560).

To prepare 6,13 dimethyl 3 rnethoxygona-l,3,l

14 tetraen 17-one hydrogenate 13-etbyl-acetoxygona-1,3, 510),8,14pentaen-17one over a 2% palladium on calcium carbonate catalystin benzene according to the manipulative procedure described above.

To prepare 13 (Zi-hydroxypropyl)-3-rnethoxygona-1,3,5(10),8-tetraen-17one hydrogenate 13,8-(3-hydroxypropyl)3methoxygona-1,3,5(10),8,14pentaen17one over a 2% palladium on calciumcarbonate catalyst in benzene according to the manipulative proceduredescribed above.

To prepare 13;? ethyl 3-methoxygona-1,3,5(10),8 tetraen-l7-onehydrogenate 13-ethyl 3 ethoxygona-l,3, 5(10),8,14pentaen17-one over a 2%palladium on calcium carbonate catalyst in benzene according to themanipulative procedure described above.

To prepare 13 phenethy1-3-propoxygonal,3,5 (10), 8tetraen17onehydrogenate 13-phenethyl-3-propoxygona-1,3,5(10),8,14-pentaenl7-one overa 2% palladium on calcium carbonate catalyst in benzene according to themanipulative procedure described above.

To prepare 1313 isobutyl 3 pentyloxygona 1,3,5 (10),8 tetraen 17-onehydrogenate 13,8 isobutyl-3- pentyloxygona 1,3,5(10),8,14 pentaen 17-oneover a 2% palladium on calcium carbonate catalyst in benzene accordingto the manipulative procedure described above.

To prepare 13 (3 hydroxypropyl) 3 cyclopentyloxygona 1,3,5(10),8 tetraen17 one hydrogenate 13p (3 hydroxypropyl) 3 cyclopentyloxygona-1,3,5(10),8,14 pentaen 17 one over a. 2% palladium ou calcium carbonatecatalyst in benzene according to the manipulative procedure describedabove.

To prepare 13,8 phenethyl 3 hydroxygona 1,3,5 (10), 8 tetraen 17 onehydrogenate 13,/3 phenethyl- 3-hydroxygona 1,3,5(10),8,14 pentaen 17 oneover a 2% palladium on calcium carbonate catalyst in benzene accordingto the manipulative procedure described above.

To prepare 13,9 (2 diethylaminoethyl) 2,3 dimetboxygona 1,3,5( l0),8tetraen 17 one hydrogenate 1313 2 diethylarninoethyl) 2,3dirnethoxygona1,3, 5(l0),8,14 pentaen 17 one over a 2% palladium oncalcium carbonate catalyst in benzene according to the manipulativeprocedure described above.

To prepare 13/3-propyl-3-ethoxy 3 methoxygona-l,3,5 (10),8-tetraen-l7-one hydrogenate 13,3-propyl-2-ethoxy- 3 methoxygona 1,3,5(l0),8,l4-pentaen 17 one over a 2% palladium on calcium carbonatecatalyst in benzene according to the manipulative procedure describedabove.

These compounds have estrogen-ic activity, lower the blood lipid level,and are useful as intermediates in the preparation of the hormonalcompounds of the invention.

Example 1(2.-13-cetyl-3-methoxygona-1,3,5( 10),8- tetraen-17-oneHydrogenate 1313 cetyl 3 methoxygona-1,3,5(10), 8,14 pentaen 17 one(2.39 g.) in benzene (140 cc.) at atmospheric pressure with a previouslyreduced 2% palladium oxide on calcium carbonate catalyst (0.3 g.) untilone molecular equivalent of hydrogen has been absorbed. Remove thecatalyst and evaporate to obtain a residue which one crystallizes fromethanol to obtain the title product (2.4 g), as colorless crystals, M1).5456"; ultraviolet absorption peak at 278 ma (e 11,500).

C34H52O2, calculated: C, 82.85%; H, 10.65%. Found: C, 82.75%; H, 10.75%.

This compound has estrogenic activity, and is useful as an intermediatefor preparing the hormonal compounds of this invention.

Example 1l.-13/3-methyl-3hydroxygona-l,3,5(10),8- tetraen-17-oneHydrogenate 13p' methyl 3 acetoxygona-l,3,5(10), 8,14 pentaen 17 one(0.05 g. obtained by the acetylation of13-methyl-3-hydroxygona-1,3,5(10),8,14-pentacn l7-one using pyridine andacetic anhydride) in benzene (l5 cc.) at atmospheric pressure using a10% palladizcd charcoal catalyst (0.025 g.). Hydrogenation slows downmarkedly after the requisite quantity of hydrogen for monohydrogenationhas been absorbed. Remove the catalyst by liltration and evaporate thesolvent to obtain as residue the crude title product.

Immediately take the product up in methanol (4 cc.), add 3 N sodiumhydroxide solution (l cc.) and shake the mixture for 20 minutes. Acidifyand extract with ether to obtain a product which one dissolves inbenzene and passes through a column of activated fullers earth.Evaporate the resulting solution and recrystallize the residue frommethanol to obtain the title product, M.P. 22S-227; ultravioletabsorption peak at 278 una (e 15,300).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds f thisinvention.

Example 12.-13-methyl-3-hydroxygona-1,3,5(10),8 tetraen-17-one Shake13,8 methyl 3 hydroxygona-l.3,5(10),8,14- pentaen-17-one (0.05 g.) inbenzene (25 cc.) in hydrogen at atmospheric pressure using a palladizedcharcoal catalyst (0.025 g.). Hydrogenation becomes very slow when 1.1moles hydrogen has been absorbed. Filter and evaporate to obtain thetitle product (0.035 g.), recrystallize from methanol to get pale bluecrystals, M.P. 22S- 228, melting to a red liquid; ultraviolet absorptionpeak at 280 mit (e 12,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 13 .-13-ethyl-3-hydroxygona-1,3,5 10) ,8- tetraen-17-oneHydrogenate 13,3 ethyl 3 hydroxygona-1,3,5(10), 8,14 pentaen 17 one (0.5g.) in benzene (25 cc.) at atmospheric pressure using a 10% palladizedcharcoal catalyst (0.025 g.). After the absorption of 1.1 molarequivalents of hydrogen, hydrogenation becomes very slow; remove thecatalyst by filtration and evaporate the filtrate to obtain the titleproduct which crystallizes from methanol in colorless plates (0.35 g.),M.P. 23S-239; ultraviolet absorption peak at 280.5 m/.L (e 15,500).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 14.-,13-ethyl-3-acetoxygona-1,3,5(10),8 tetraen-17-oneHydrogenate 13,8 ethyl 3 acetoxygona-1,3,5(10), 8,14 pentaen 17 one (1.8g.) dissolved in benzene (25 ml.) at atmospheric pressure in thepresence of 10% palladized charcoal (100 mg). After 1.1 molarequivalents of hydrogen has been absorbed (ca. l2 hours) lilter off thecatalyst, evaporate the filtrate under reduced pressure andrecrystallize the residue from ethanol. Filter the red product throughFlorisil (60 g.) with benzenepetroleum (3:1), remove the solvent andrecrystallize the product from 'ethanol to obtain the title product,M.P. 132.5-134.5; ultraviolet absorption peak at 277 my. (e 12,800).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 15.-13,8-ethyl-3-hydroxygona-1,3,5 (10),8 tetraen-17-0ne Heat l3ethyl 3 acetoxygona 1,3,5(l0),8tetraen 17-one (0.5 g.) and sodiumhydroxide (1.2 g.) in water (10 cc.) and methanol (30 cc.) at 50 for 20minutes in an atmosphere of nitrogen. Cool the mixture, acidify withdilute acetic acid and extract with a mixture of ether and benzene.Wash, dry and evaporate the organic extract to obtain the titleproducts, M.P. 266-270; ultraviolet absorption peak at 278.5 nm (e13,200).

This compound has cstrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Treat 13-ethyl-3-hydroxygona-1,3,5( l0) ,8-tetraen-17- one (0.2 g.) inmethanol (20 cc.) with an excess of an ethereal solution ofphenyldiazomethane. After 18 hours add acetic acid (3 cc.) andevaporate. Filter the residue through a column of alumina (l5 g.) andevaporate the solvent to obtain the title product; ultra-violetabsorption peak at 280 ma (e 15,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 19.-13-methyl-3-methoxy-D-homogona-1,3,5 (10) ,8-tetraen-17a-olAdd 13-methyl-3-methoxy-D-homogona-1,3,5(10),8 tetraen-17a-one to sodiumborohydride (7 g.) in methanol (400 cc.) and reflux for 30 minutes.Acidify the mixture with 50% aqueous acetic acid and evaporate almost todryness. Add water and extract the product with ether. Wash, dry andevaporate the ethereal solution and crystallize the residue from ethanolto obta-in the title product, (19 g.), M.P. 83-86; ultravioletabsorption peak at 278 ma (e 15,800); infrared absorption peaks at2.96,. and 6.22p..

To prepare 7,13-dimethyl-3-methoxygona-1,3,5 l0) ,8- tetraen-17-ol treat7,13-dimethyl-3-methoxygona-1,3,5 (10),8tetraen17one with sodiumborohydride according to the manipulative procedure described above.

To prepare 13-methylgona-1,3,5(l0),8-tetraen-3,17,B diol treat13-methyl-3-hydroxygona-1,3,5 (10),8tetraen 17-one with sodiumborohydride according to the manipulative procedure described above.

To prepare 13-ethyl-2,3-dimethoxygona-1,3,5(10),8 tetraen-17-ol treat13-ethyl-2,3-dimethoxygona-1,3,5 (10),8tetraen17one with sodiumborohydride according to the manipulative procedure described above.

To prepare 13-ethyl-3-ethoxygona-1,3,5(10),8tetrae'n 17j8-ol treat13=ethyl3ethoxygona1,3,5( l0),8tetraen17 one with sodium borohydrideaccording to the manipulative procedure described above.

To prepare 13-iso'butyl-3-pentyloxygona-1,3,5(l0),8 tetraen-17-ol treat13-isobutyl-3-pentyloxygona-1,3,5 (10),8-tetraen17-one with sodiumborohydride according to the manipulative procedure described above.

To prepare 13-(3-dimethylaminopropyl)1,3-dimethoxygona-l,3,5(l0),8tetraen17ol treat 13-(3-dimethylaminopropyl)1,3,dimethoxygona1,3,5(l0),8-tetraen 17-one with sodium borohydrideaccording to the manipulative procedure described above.

These compounds have estrogenic activity, lower the blood lipid level,and are useful as intermediates in the preparation of the hormonalcompounds of the invention.

Example 20.-1 3,6-methyl-3-methoxygona-1,3,5 10 8-tetraen-l7-ol Addsodium borohydride (0.5 g.) to a solution of 13- methyl3-methoxygona-l,3,5(10),8-tetraen17one (2.9 g.) in ethanol (50 cc.),reflux for 10 minutes and then leave at room temperature Ifor 1/2 hour.Acidify with glacial acetic acid and evaporate to dryness under reducedpressure. Treat the residue with water, ether-extract and wash and dry.Evaporate the extracts. Recrystallize the residue from methanol toobtain the title product (2.3 g.), M.P. 133-135.

C1gH2.,Oy calculated: C, 80.2%; H, 8.5%. Found: C, 80.4%; H, 8.4%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing thc hormonal compounds ofthis invention.

1 7 Example 21.-13-ethyl-3-methoxygona-1,3,5( 10), 8-tetraen-17olHydrogenate 13-ethyl3methoxygona1,3,5 l0),8, 14 pentaen-17-ol (0.31 g.)and recrystallize the product from hexane-ethyl acetate to obtain thetitle product; u1- traviolet absorption peak at 280 mu (e 15,000).

This compound has estrogenic ectivity, lowers the blood lipid level,.and is useful as an intermediate for preparing the hormonal compoundsof this invention.

Example 22.-13-ethyl-3-methoxygona-1,3,5(10), 8-tetraen-17-one Add13*ethyl-3-methoxygona1,3,5 10) ,S-tetraen-17- one (16.8 g.) slowly to asolution of sodium borohydride (6 g.) in methanol (500 cc.) and swirlthe mixture which boils spontaneously. When all the material has beenadded and the reaction has subsided, add acetic acid (15 cc.). Reducethe mixture in volume by evaporation of most of the solvent, add waterand extract the product with ether. Evaporate the washed and driedextracts to obtain a crude crystalline product (16.8 g.), M.P. 102-105on recrystallization from acetronitrile.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Reduce l3-ethyl-3-methoxy D-homogona-l,3,5(l0),8 tetraen-17a-one (20.9g.) exactly as described for the preparation of the 13methyl compound toobtain the title product (20 g.), M.P. 110-112; infrared absorptionpeaks at 2.9,u and 6.23,u.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 24.-1 3-propyl-3-methoxygona-1,3,5( 10) S-tetraen- 1 718-011Hydrogenate 13/3 propyl-3-methoxygona-1,3,5(10),8, 14-pentaen-l7ol (0.32g.) and recrystallize the product from hexaneethyl acetate to obtain thetitle product, ultraviolet absorption peak at 280 mp. (e 15,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 25.-13-propyl-3-methoxygona-1,3,5(10), 8-tetraenl 7f3-Ol Add 13-propyl-Smethoxygona1,3,5 10) ,8-tetraen17 one (3.5 g.) to a solution ofsodium borohydride (1.16 g.) in methanol (120 cc.). Heat the reactionmixture to reflux with stirring for 30 min. Concentrate the resultingsolution, adjust its pH to 6 with aqueous acetic acid and filter off theresulting white precipiate which is the title product, (3.1 g.), M.P.134-138; ultraviolet absorption peak at 278 mp. (e 15,350); infraredshowed a band due to hydroxyl but no ketone present.

C21H28O2, calculated: C, 80.7%; H, 9.0%. Found: C, 80.5%; H, 9.0%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermedi-ate for preparing the hormonal compounds ofthis invention.

Add sodium borohydride (12.1 g.) to 13butyl3methoxygona1,3,5(10),8tetraen 17 one (36.2 g.) in ethanol (1200 cc.) andreflux the mixture for l hour. On cooling, acidify the mixture withaqueous acetic acid and evaporate to dryness under reduced pressure. Addwater to the residue and extract the product with ether. Work up in theusual manner to obtain a residue; recrystallize from hexane to obtainthe 13-n-butyl-title product (26.9 g.), M.P. 90-100; ultravioletabsorption peak at 279 mu (e 15,600); infrared :absorption peak at2.88/7, to absorption in the 5.71-5.88 region.

C22H30O2, calculated: C, 80.9%; H, 9.3%. Found: C, 81.0%; H, 9.0%.

This compound possesses estrogenic activity, lowers the blood lipidlevel, and is useful as an intermediate for preparing the hormonalcompounds of this invention.

Example 27.--13-isobutyl-3-methoxygona1,3,5( 10) ,8- tetraen-17-ol To astirred solution of sodium borohydride (6.0 g.) in methanol (500 cc.under nitrogen) add 13-isobutyl- 3-methoxygona 1,3,5(10),8 tetraen 17one (17 g.). Gently heat the reaction mixture for one minute to initiatethe reaction and then allow to stand for one hour at room temperature.After adding cautiously glacial acetic acid (20 ce), concentrate thesolution in vacuo to 1/3 of its volume followed by addition of water.Extract the product with ether. Wash the ethereal solution successivelywith water, sodium bicarbonate, and water, and dry. Evaporate the etherto obtain 13-isobutyl-3-methoxygona-1,3,5(l0),8tetraen17ol ast a gum(17.0 g.; 99%); ultraviolet absorption peak at 278 mp. (e 14,560).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 28.-13-cetyl-3-rnethoxygona-1,3 ,5( 10),8

tetraen- 17,8-01

Stir a solution of 13cetyl3methoxygona1,3,5(10), 8-tetraen-17-one (0.60g.) and sodium borohydride (0.20 g.) in ethanol cc.) for 2 hours andleave overnight. Reflux with stirring for 2 hours, cool, and add anexcess of 50% aqueous acetic acid. Evaporate the mixture to drynessunder reduced pressure `and partition the residue between ether andwater. Work up in the usual manner to obtain the title product as a gum;infrared absorption peak at 278 mit.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Shake 13-ethylgona1,3,5(10),8,14 pentaene-3,17 diol (0.28 g.) in benzene(35 cc.) with 10% palladized charcoal (300 mg.) in an atmosphere ofhydrogen until 25 cc. of hydrogen has been absorbed. Filter olrthecatalyst, evaporate the solvent and recrystallize the residue frommethanol to obtain the title product, M.P. 234- 238; ultravioletabsorption peak at 280 mp. (e 14,200).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Hydrogenate 13propy1gona-1,3,5(10),8,14pentaene- 3,17-diol (0.31 g.)exactly as described in the previous example to obtain the titleproduct, M.P. 210-2l8; u1- traviolet absorption peak at 280 mu (e12,000).

This compound possesses estrogenic activity, lowers the blood lipidlevel, and is useful as an intermediate for preparing the hormonalcompounds of this invention.

Methylate 13 -ethyl-S-methoxygona- 1 ,3,5 (10),8tetra ene-17-ol (l g.)in methylene chloride (50 cc.) containing boron triuoride etherate (0.1cc.) with diazomethane (from N-nitrosomethylurea 3.1 g.) in methylenechloride (60 cc.). Leave the mixture for 5 minutes, filter, and wash thefiltrate with aqueous sodium bicarbonate, 10% aqueous potassiumhydroxide, and water, and dry. Recrystallize the product from hexanecontaining a few drops of ethanol to obtain the title product Example32.-13-ethyl-3,l7-dirnethoxygona- 1,3,5( l) ,S-tetraene Shake13-ethyl-3,17-dimethoxygona-1,3,5 10) ,8, 14- pentaene (1 g.) in benzene(50 cc.) with 2% palladium on calcium carbonate (0.5 g.) in anatmosphere of hydrogen until 1 molar equivalent of hydrogen (85 cc.) hasbeen absorbed. Filter the catalyst and evaporate the solvent to obtainthe title product, 94-97; ultraviolet absorption peak at 278 ma (e16,400).

This compound possesses estrogenic activity, lowers the blood lipidlevel, and is useful as an intermediate for preparing the hormonalcompounds of this invention.

Methylate 13-butyl 3 methoxygona 1,3,5(10),8 tetraen17ol (1 g.) inmethylene chloride (50 cc.) with diazomcthane. Recrystallize the crudeproduct from ethanol and then take up in benzene; chromatograph onneutral alumina. Benzene-ether (2:1) elutes a fraction which onerecrystallizes from ethanol (6 cc.) to obtain the title product (.2 g.),M.P. 87; ultraviolet absorption peak at 279 ma (e 16,700).

C23H32O2, calculated: C, 81.1%; H, 9.5%. Found: C, 81.0%; H, 9.4%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 34.13-ethyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8-tetraeneHydrogenate l3ethyl3methoxy 17,17ethylenedioxygona-l,3,5(10),8,14-pentaene (2.0 g.) in benzene (70 cc.)at atmospheric pressure using a 5% palladium on calcium carbonatecatalyst (0.70 g.). Uptake of hydrogen ceases after 150 cc. has beenabsorbed. Isolate the product and recrystallize from 95% ethanol toobtain the title product (1.3 g.), M.P. 13S-137; ultraviolet absorptionpeak at 278 mp. (e 15,100).

C22H28O3, calculated: C, 77.6%; H, 8.3%. Found: C, 77.5%; H, 8.6%.

This compound possesses estrogenic activity and blood lipid loweringactivity, and is useful as an intermediate for preparing the hormonalcompounds of this invention.

To prepare 6,13-dimethyl-3-methoxy-l7,17-ethylenedioxygona 1,3,5(10),8tetraene hydrogenate 6,13-dimethyl-B-methoxy 17,17ethylenedioxygonal,3,5(10), 8,14-pentaene using a 5% palladium oncalcium carbonate catalyst according to the manipulative proceduredescribed above.

To prepare13,8-ethyl-1,3dimethoxy17,17-ethylenedioxygona-l,3,5(l0),8tetraenehydrogenate 13-ethyl-l,3 dimethoxy 17,17-ethylenedioxygona-l,3,5( 10 ,8,l4-pentaene using a 5% palladium on calcium carbonate catalyst accordingto the manipulative procedure described above.

To prepare 13-phenethyl-3-propoxy-17,17-ethylenedioxygona-1,3,5(),^8tetraene hydrogenate IB-phenethyl- 3propoxy17,17-ethylenedioxygona-1,3,5 10) ,8,14-pentaene using a 5%palladium on calcium carbonate catalyst according to the manipulativeprocedure described above.

To prepare 13/3-(3-hydroxypropyl)-3-cyclopentyloxy- 17,17ethylenedioxygona1,3,5(10),8tetraene hydrogenate 1313-(3-hydroxypropyl)-3-cyclopentyloxy-17,17-ethylenedioxygona-1,3,5(10),8,14pentaene using a 5% palladium oncalcium carbonate catalyst according to the manipulative proceduredescribed above.

These compounds possess estrogenic and blood lipid lowering activity andare useful as intermediates in the preparation of the hormonal compoundsof this invention. Example 3 5 .-1 3 -ethyl-3-methoxy-l7,17-(2,2dimethyl propylenedioxy)gona-1,3,5 l0) ,S-tetraeneShake 13ethyl3methoxy17,17-(2,2dimethylpropylenedioxy)gona1,3,5(10),8,14pentaene (5 g.) in benzene cc.) containing 2%palladized calcium canbonate (1.75 g.) with hydrogen at atmosphericpressure until one molecular equivalent has been absorbed. Recrystallizethe product from ethanol to obtain the title product; ultravioletabsorption peak at 276.5 mp. (613,500).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermedate for preparing the hormonal compounds of thisinvention.

Example36.-13-propyl-3-methoxy-17,17-ethylenedioxygona-1,3,5(10),8-tetraeneShake 13-propyl-3 -methoxy-17, l7-ethylenedioxygona-1,3,5(10),8,14pentaene (2.5 g.) in benzene (80 cc.) with hydrogen atatmospheric presure in the presence of a 2% palladium on calciumcarbonate catalyst (0.9 g.); hydrogen uptake ceases after the requisiteamount (161 cc.) for monohydrogenation has been absorbed. Filter andevaporate to obtain a gum, ywhich one crystallizes from ethanol toobtain the title product (1.18 g.), M.P. 119-l20; ultraviolet absorptionpeak at 27,8 my. (e 15,300).

C23H30O3, calculated: C, 77.9%; H, 8.5%. Found: C, 77.7%; H, l8.5%.

This compound possesses estrogenic and blood lipid lowering activitiesand is useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 37.-1 3 ,-ethyl-S -methoxy-l 7a-ethynyl gona- 1,3, 5( 10),8-tetraen-17-ol To 13 ethyl3-methoxygonal,3,5(10),8-tetraen-17- one(5.0 g.) in tetrahydrofuran (l0 cc.) add 200 cc. of lithium aluminumacetylide suspension and reux the mixture for 4 hours. Add ice waterwith stirring, follow by 3 N sulphuric acid to dissolve the resultingprecipitate, and work up the product with ether in the usual Way, toobtain the title product (5.0 g.); ultraviolet absorption peak at 276 ma(e 13,300).

This compound possesses estrogenic and blood lipid lowering activity andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Add 13,8 ethyI-S-methoxygona-l,3,5(10),\8tetraenl7 one (92 g.) inaniline (300 cc.) with stirring to lithium acetylide (from commerciallithium amide, 50 g.) in aniline (500 cc.) under an acetyleneatmosphere. Pass acetylene into the mixture with stirring for 3 days.Add water and extract the mixture with ether; free the extracts fromaniline by -washing with 10% sulphuric acid, and isolate the product toobtain the title product as a gum ('88 g.); infrared absorption peaks at2.75, 3.03/t.

This compound has estrogenic and blood lipid lowering activity and isuseful as an intermediate for preparing the hormonal compounds of thisinvention.

To a stirred suspension of lithium acetylide (42.4 g.) in a mixture ofdioxan (240 cc.), ethylenediamine (10 cc.), and dimethylacetamide (250cc.) add a solution of 1318 ethyl 3-methoxygona-1,3,5(10),8tetraen17one(66.6 g.) in dimethylacetamide (450 cc.) in an atmosphere of acetylene.Continue stirring for an additional 20 hours (under acetylene). Pour thereaction mixture into crushed ice (1.5 kg.) and extract with four 200cc. portions of benzene. Wash the combined extracts with sulfuric acidand water and dry. Evaporate the solvent to obtain a crude oil which onedissolves in methanol (450 21 cc.) and treats with charcoal (16.5 g.).After concentrating the filtrate to 300 cc. add water (45 cc.) and coolto obtain the title compound (62.4 g., 86%). Recrystallization frommethanol furnishes an analytical sample, M.P. lOl-103; ultravioletabsorption peak at 278 my. (e 16,- 100); infrared absorption peaks at2.79, 3.04, 3.53, 4.181,1..

C22H26O2, calculated: C, 82.3%; H, 8.3%. Found: C, 82.0%; H, 8.1%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

To prepare 13,8-cety1-3-methoxy-17a-ethynylgona-1,3,5 (l),8-tetraen17oltreat 13-cetyl-3-methoxygona-1,3, 5(10),8tetraenl7one with lithiumacetylide according to the manipulative procedure described above.

To prepare I6,13-dimethyl-3-methoxy-17a-ethynylgona- 1,3,5,IS-teraen-l7-ol treat6,13,8-dimethyl-3-methoxygona-1,3,5(10),8tetraen17one with lithiumacetylide according to the manipulative procedure described above.

To prepare 7,13dimethyl3methoxy17a-ethynylgona- 1,3,5 10),8-tetraen-17-ol treat7,13,8dimethyl3methoxygona-1,3,5(10),8tetraen-17one with lithiumacetylide according to the manipulative procedure described above.

To prepare 13 rnethyl2,3dimethoxy17a-ethynylgona-1,3,5(10),=8tetraen17,8ol treat13,3-methyl-2,3di1methoxygonal,3,5(10),8tetraenl7-one with lithiumacetylide according to the manipulative procedure described above.

To prepare 13,8-ethyl-3-ethoxy-17a-ethynylgona-1,3,5 (10),8tetraen17oltreat 13ethyl3ethoxygona1,3,5 (l0),8tetraenl7one with lithium acetylideaccording to the manipulative procedure described above.

To prepare 13,8-phenethyl-3-propoxy-17a-ethynylgona- 1,3,5(l0),\8tetraen17\ol treat13-phenethyl-3-propoxygonal,3,5(10),8tetraen17-one with lithiumacetylide according to the manipulative procedure described above.

To prepare 13,3-(3-hydroxypropyl)3cyclopentyloxy17aethyny1gona-1,3,5(10),8tetraen17ol treat 13-(3- hydroxypropyl) 3cyclopentyloxygona 1,3,5(10),8 tetraen-17-one with lithium acetylideaccording to the manipulative procedure described above.

To prepare 13-(2-diethylaminoethyl) -2,3dimethoxy17a-ethynylgona-1,3,5(l0),8tetraen17ol treat 13,8-(2- diethylaminoethyl)2,3 dimethoxygona 1,3,5(10),8 tetraen-17-one with lithium acetylideaccording to the manipulative procedure described above.

These compounds have estrogenic activity, and are useful in thepreparation of the hormonal compounds of this invention.

To a stirred suspension of lithium carbide (2.5 g.) in a mixture ofdioxan (4() cc.), ethylenediamne (10 cc.), and dimethylacetamide (50cc.) add a solution of 13,3- ethyl-3-methoxygona-1,3,5(10),8tetraen17one(5 g.) in dimethylacetamide (50 cc.) in an atmosphere of acetylene.Continue stirring for an additional 20 hours under acetylene. Pour thereaction mixture into crushed ice (200 g.) and extract with ether. Washthe ethereal solution with sulfuric acid and water, and dry. Evaporatethe ether to obtain a crude oil which one dissolves in methanol (50cc.); treat with charcoal (6 g.) and filter. Concentrate the filtrate toabout '1/2 of its volume, add water (6 cc.), cool to obtain the titleproduct (4.2 g., 77%). Recrystallize from methanol, M.P. lOl-3;ultraviolet absorption peak at 278 my. (616,100); infrared absorptionpeaks at 2.79, 3.04, 3.53, 4.81u.

This compound possesses estrogenic and blood lipid lowering activity andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Add 13-propyl-3-rnethoxygona-l,3,5(10),8tetraen17 one (2.0 g.) inaniline (30 cc.) with stirring to lithium acetylide (from lithium, 1 g.)in aniline (60 cc.) under an acetylene atmosphere. Pass a vigorousstream of acetylene in-to the mixture with stirring for 26 hours. Workup to obtain the title product as a red gum (2.0 g.); infraredabsorption peaks at 2.80, 305,1..

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Add l3/3-butyl-3-methoxygona-1,3,5( 10),8tetraen17 one (3.5 g.) inaniline (35 cc.) with stirring to lithium acetylide (from commerciallithium amide, 4 g.) in aniline (55 cc.) under an acetylene atmosphere.Pass acetylene into the mixture with stirring for 40 hours. Work up toobtain the title product as a red gum (3.7 g.); infrared absorptionpeaks at 2.93, 3.08, 4.59a.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Shake 13,8-ethyl-3-methoxy-17aethynylgona1,3,5 10 8-tetraen-l7-0l 1.9g.) in benzene (100 cc.) with hydrogen at atmospheric pressure in thepresence of a prereduced 2% palladium on calicum carbonate catalyst (0.6g.) until no more hydrogen is absorbed. Hydrogenation ceases when therequisite amount of hydrogen for selective saturation of the ethynylgroup has been absorbed. Filter and evaporate the solvent to obtain acrystalline residue which one recrystallizes from methanol, to obtainthe title product (1.5 g.), M.P. 139-140; ultraviolet absorption peak at276 ma (e 15,500); infrared absorption peak at 2.79,t.

This compound has estrogenic activity, and is useful in the preparationof the hormonal compounds of this invention.

To obtain 13,8 cetyl 3 methoxy 17a ethylgona- 1,3,5(10),8 tetraen 17p?of hydrogenate 13,9 cetyl- 3 methoxy 17a ethynylgona 1,3,5 (10),8tetraen- 17,9ol using a prereduced 2% palladium on calcium carbonatecatalyst according to the manipulative procedure described above.

To obtain 6,13 dimethyl 3 methoxy 17a ethylgona 1,3,5(10),8 tetraen 17,8ol hydrogenate 6,13/3- dimethyl 3 methoxy 17a ethynylgona 1,3,5( l0),8-tetraen-17-ol using a prereduced 2% palladium on calcium carbonatecatalyst according to the manipulative procedure described above.

To obtain 7,13,8 dimethyl 3 methoxy 17a ethylgona 1,3,5(l0),8 tetraen17,8 ol hydrogenate 7.13/3- dimethyl 3 methoxy 17a ethynylgona1,3,5(10),'8 tetraen-17,801 using a prereduced 2% palladium on calciumcarbonate catalyst according to the manipulative procedure describedabove.

To obtain 13,3,17a diethyl 2,3 dlimethoxygona-l,3,5 (10),8 tetraen 17,9ol hydrogenate 13,8 ethyl 2,3- dimethoxy 17a ethynylgona 1,3,5(10),8tetraen- 17-ol using a prereduced 2% palladium on calcium carbonatecatalyst according to the manipulative procedure described above.

To obtain 13,8 phenethyl 3 propoxy 17a ethylgona 1,3,5(10),8 tetraen17,8 ol hydrogenate 13- phenethyl 3 propoxy 17a ethynylgona 1,3,5(10),8tetraen-17801 using a prereduced 2% palladium on calcium carbonatecatalyst according to the manipulative procedure described above.

23 hydrogenate 13 (3 hydroxypropyl) 3 cyclopentyloxy 17u ethynylgona1,3,5(10),8 tetraen 1718 o1 using a prereduced 2% palladium on calciumcarbonate catalyst according to the manipulative procedure describedabove.

To obtain 13/3 (2 diethylaminoethyl) 2,3 dimethoxy 17a ethylgona1,3,5(l0),8 tetraen 17,3 ol hydrogenate 13,3 (2 diethylaminoethyl) 2,3dimethoxy 17a ethynylgona l,3,5(10),8 tetraen 17,6 ol using a prereduced2% palladium on calcium carbonate catalyst according to the manipulativeprocedure described above.

These compounds possess estrogenic activity, and are useful asintermediates in the preparation of the hormonal compounds of thisinvention.

Example 44.-1 3 -propyl-3 -methoxy- 1 7a-ethyl gona- 1,3,5( 108-tetraenl 7-ol Shake 13/8 propyl 3 methoxy 17a ethynylgona-1,3,5(l),8tetraenl7ol (1 g.) in benzene (100 cc.) with hydrogen atatmospheric pressure in the presence of a prereduced 2% palladium oncalcium carbonate catalyst (0.35 g.). Hydrogenation is interrupted afterthe requisite amount of hydrogen for selective saturation of the ethynylgroup has been absorbed; filter and evaporate to obtain a residue;crystallize from methanol to obtain the title product (0.5 g.), M.P.106-108; ultraviolet absorption peak at 278 my. (e 14,700); infraredabsorption peak at 2.80n.

This compound possesses estrogenic activity, and is useful as anintermediate in the preparation of the hormonal compounds of thisinvention.

Example 45.-13-butyl-3methoxy1,7.t-ethylgona 1,3,5 110) ,S-tetraen-17-olShake 13,8-butyl-3 `methoxy-17otethynylgona1,3,5 10) S-tetraen-l7l3-ol(3.7 g.) in benzene (150 cc.) with hydrogen at atmospheric pressure inthe presence of a prereduced 2% palladium on calcium carbonate catalyst(1.2 g.) until the amount of hydrogen required for selective saturationof the ethynyl group has been absorbed. Crystallize the red gum (3.7 g.)obtained on filtration and evaporation from methanol. 'to obtain crudeproduct (2.9 g.), a portion is further recrystallized from aqueousacetonitrile to give the pure compound, M.P. 72-76; ultravioletabsorption peak at 278 mu (e 15,600); infrared absorption peak at2.97/t.

,This compound possesses estrogenic activity, and is useful as anintermediate in the preparation of the hormonal compounds of thisinvention.

To a suspension of magnesium turnings (20 g.) in tetrahydrofuran (50cc.) add several milliliters of a solution of allyl bromide (11.8 g.) intetrahydrofuran (225 cc.) and initiate the reaction by crushing a pieceof the suspended magnesium with a glass rod and add a small crystal ofiodine. Slowly add the rest of the solution of allyl bromide intetrahydrofuran over 30 minutes followed by the dropwise addition of asolution of 13/8-ethyl-3- methoxygona1,3,5(10),8tetraen 17 one intetrahydrofuran (1 liter) and allyl bromide (220 g.) over a period of 45minutes. Reflux the reaction mixture for 3 hours, cool to and add 20%aqueous ammonium chloride with vigorous stirring. Separate the organiclayer, extract the aqueous layer with ether (400 cc.) and add ether (500cc.) to the combined organic extracts which are then washed with coldwater (5X 300 cc.), dried, the solvent evaporated and the residuerecrystallized from n-hxane to obtain the title product (51 g., 88%),M.P. 123-125; ultraviolet absorption peak at 280 mn (E 18,300); infraredabsorption (KBr disc) peaks at 2.88, 3.43, 6.12, 6.23, 6.36, 6.67,u.

C23H30O2, calculated: C, 81.6%; H, 8.92%. Found: C, 81.55%; H, 8.81%.

This compound possesses estrogenic activity, and is useful as anintermediate in the preparation of the hormonal compounds of thisinvention.

Example 47.-13,8-ethyl-3-methoxy-17apropylgona-l,3,5 (10),8-tetraen-17-ol Shake 13-ethyl-3-methoxy-l7a-allylgona 1,3,5 l0),8tetraen-17-ol (50 g.) with prereduced 2% palladium on calcium carbonatecatalyst (25 g.) in benzene (500 cc.) in an atmosphere of hydrogen untilone molecular equivalent of hydrogen has been absorbed (3.6 1.). Filteroff the cata-lyst, evaporate the solvent and recrystallize the residuefrom hexane to obtain the title product. (40 g., 80%), M.P. 137-139;ultraviolet absorption peak at 278 m/.t (e 16,800); infrared absorption(KBr disc) peaks at 2.95, 3.5, 6.25, 6.37, 6.68,u.

This compound possesses est-rogenic activity, and is useful as anintermediate in the preparation of the hormonal compounds of thisinvention.

Dissolve the crude reduced diketone obtained by catalytic hydrogenationof 5-(Z-m-methoxyphenylethyl)8 tmethyl-6-oxon5(lo-Octalin-1-one inmethanol (16 cc.) containing concentrated hydrochloric acid (4 cc.).Keep the solution for 3 hours at room temperature and then 1 hour at 0C. Filter the crystalline precipitate of cyclodehydrated product andrecrystallize from ethyl acetate to obtain D-homo-13-methyl-3methoxygona 1,3,5(l0),9 (11)-tetraen-l7a-one (0.96 g., 51%), M.P. 1725C.

C20H24O2, calculated: C, 81.0%; H, 8.2%. Found: C, 80.8%; H, 8.1%.

This compound possesses estrogenic activity, lowers the blood lipidlevel and is useful as an intermediate in the preparation of thehormonal compounds of this invention.

Example 49.-D-homo-13-methyl-3 -methoxygona-1,3,5(10),9(11)-tetraen-17a-one Reux the crude reduced diketone (1 g.)starting `material of the previous example in ethanol (25 cc.) with 20%sulphuric acid (0.2 cc.) for 2 hours. Cool, and filter the precipitatesolid (273 mg.) and recrystallize from ethanolethyl acetate mixture toobtain D-homo-13-methyl-3- methoxygona-l,3,5(l0),9(11)-tetraen-17a-one.

This compound possesses estrogenic and lblood lipid lowering activityand is useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 50.-D-homo13-methyl-3-methoxygona-l,3 ,5

( 10 ,9 1 1) tetraen-17a-one :and D-homo-13-methyl- 3-methoxygona-1,3,5(l0) ,8-tetraen-l7a-one Reux the crude reduced diketone (0.5 g.) startingmaterial of the previous example in ethanol (25 cc.) with 20% sulphuricacid 10 cc.) for 2 hours; add water to the cooled solution and etherextract the mixture. Evaporate the washed and dried ether extract andobtain a crystalline residue (332 mg), melting over the range 11S-149,with ultraviolet absorption characteristics identical with that of themixed dehydro compounds.

These compounds possess estrogenic and blood lipid lowering activity andare useful as intermediates in the preparation of the hormonal compoundsof the invention.

Example 5 l .-Dhomo-l 3amethyl-3-methoxygona-1,3,5 10 ,9 l 1 -tetraen-17a-one Keep 5-(Z-m-methoxyphenylethyl) 9 methyl trans- Decalin-1,6dione(0.5 g.) in methanol (8 cc.) containing l0 N-hydrochloric acid (2 cc.)for 3 hours at room temperature, then cool to 0 C. for an hour.Recrystallize the filtered precipitate from ethanol-ethyl acetatemixture, to obtain D-homo-l3methyl3methoxygona1,3,5( 10),9(ll)tetraenl7aone (0.32 g., 68%), M.P. 172-l75 C.

This compound possesses estrogenic activity, lowers the blood lipidlevel, and is useful as an intermediate for preparing the hormonalcompounds of this invention.

Example 52.-1 3-methyl-3-methoxygona l,3,5( 10) ,9 (11)-tetraen- 17oneAllow the diketone 4-(2 m methoxyphenylethyl) 8- methyl transhexahydroindan-1,5 dione (0.77 g.) in methanol (25 cc.) and concentratedhydrochloric acid (4 cc.) to stand overnight at 0 C. Treat the mixturewith water (50 cc.) and extract with a mixture of ether and benzene.Evaporate the -washed and dried extracts to leave a gum whichcrystallizes (0.65 g.). Recrystallize from a mixture of ethyl acetateand ethanol to obtain lS-methyl- 3rnethoxygona-1,3,5(10),9(l1) tetraen17 one, M.P. 144-148 C.

This compound possesses estrogenic and blood lipid lowering activity andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 53,-13-ethyl-3-methoxygona-1,3,5(l0),9(1l)- tetraen-17-one Allowthe diketone 4-(2-m methoxyphenylethyl) 3ethyl-transhexahydroindan-l,S-dione (0.8 g.) in methanol (25 cc.) andconcentrated hydrochloric acid (4 cc.) to stand 15 hours at 0 C. Filterthe precipitate and recrystallize from methanol to givel3-ethy1-3-methoxygonal,3,5(10),9(11)-tetraene-17-one; ultravioletabsorption peak at 264 m-,a (e 18,000); infrared absorption peak at5.78m

This compound possesses estrogenic and blood lipid lowering activity andis useful as an intermediate for preparing the hormonal :compounds ofthis invention.

Add concentrated hydrochloric acid to a solution of4(2-mmethoxyphenylethyl)-8 ethyl 5 oxo 5,6,7,8 tetrahydroindan-l-ol (0.5g.) in methanol (10 cc.) until the solution becomes permanently cloudy.Scratch the solution with a seed of product, filter the precipitate andrecrystallize from hexane to obtain 13ethyl3methoxygona-1,3,5(10),9(11)tetraen17ol; ultraviolet absorption peak at 264 ma(e 17,600).

This compound possesses estrogenic and blood lipid lowering activity andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 56.-13,8-ethyl-3-methoxygona-1,3,5(l0),9(11)- tctraen-17-ol Reux13 ethyl-3-methoxygona-1,3,5 10),8tetraene 17,6-01 (0.5 g.) in ethanol(15 cc.) and concentrated hydrochloric acid (3 cc.) for 2 hours. Dilutethe cooled solution with water and collect the product in ether. Wash,dry and evaporate the ethereal solution and recrystallize the residuefrom methanol to obtain 13 -ethyl3methoxy gona-1,3,5(10),9(11)tetraen-l7-ol; ultraviolet absorption peaks at 265 my. (e 15,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

26 Example 57.-13-ethyl-3-methoxygona-1,3,5(l0),9(11) tetraen-l7-oneTreat 13ethyl3methoxy17,17 ethylenedioxygona- 1,3,5(l0),8tetraene (0.5g.) exactly as described in the previous example to obtain13-ethyl-3-methoxygona- 1,3,5(l0),9(11)tetraen17one, M.P. 134-l38;ultraviolet absorption peak at 266 mp. (e 15,000); infrared absorptionpeaks at 5.7811..

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example Sarnen-bums -f methoxygona 1,3,s(10), 9( l 1)-tetraen-17-oneReux 13 -n-butyl-3-methoxygona-l,3,5 l0) ,S-tetraen- 17-one (0.2 g.) inmethanol (25 cc.) and -concentrated hydrochloric acid (l5 cc.) for 20minutes. Remove most of the solvent under reduced pressure, add waterand extract the mixture with ether. Evaporate the washed and driedextracts and crystallize the pink gum from methanol to obtain 13butyl 3methoxygona 1,3,5(10),9(ll)- tetraen-17-one (0.075 g.), M.P. l09-114;ultraviolet absorption peaks at 264 mit (617,800).

To prepare 13-isopropyl `3 methoxygona-l,3,5(10), 9(11)tetraenl7onetreat 13-isopropyl-3methoxygona- 1,3,5(10),8tetraenl7one with methanolichydrochloric acid according to the manipulative procedure describedabove.

To prepare 13-is0butyl 3 methoxygona-l,3,5(l0), 9( 1l )-tetraen17onetreat 13 isobutyl3-methoxygona- 1,3,5(10),8-tetraen17one with methanolichydrochloric acid according to the manipulative procedure describedabove.

To prepare l3-cetyl-3-methoxygona-1,3,5(l0),9(11) tetraen-l7-one treat13cetyl3methoxygona-1,3,5 (10), 8-tetraen-l7-one with methanolichydrochloric acid according to the manipulative procedure describedabove.

To prepare 6,13-dimethyl-3-methoxygona 1,3,5(10), 9(1l)tetraen17onetreat 6,13-dimethyl 3 methoxygona-1,3,5(l0),8tetraen17one withmethanolic hydrochloric acid according to the manipulative proceduredescribed above.

To prepare 7,13-dmethyl-3-methoxygona-1,3,5 (10), 9(11)-tetraenl7onetreat 7,13dimethyl 3 methoxygona-l,3,5(10),8tetraen17one with methanolichydrochloric acid according to the procedure described above.

To prepare 13ethyl-2,3 'dimethoxygona 1,3,5(10), 9(11)tetraen17one treatl3,B-ethyl-2,3-dimethoxygona- 1,3,5 (10),8tetraen 17 one with methanoland hydrochloric acid according to the manipulative procedure describedabove.

To prepare 13ethyl1,3 dimethoxygona 1,3,5(10), 9( 11)-tetraen-17-onetreat l3-ethyl-1,3-dimethoxygona- 1,3,5(1G),8tetraenl70ne with methanoland hydrochloric acid according to the manipulative procedure describedabove.

To prepare 13-methyl-3-acetoxygona-1,3,5(10),9(1l) tetraen-17one treat13-methy1-3-acetoxygona-l,3,5(10), 8-tetraen-l7-one with methanol andhydrochloric acid according to the manipulative procedure describedabove.

To prepare 13,8-(3hydroxypropyl) 3 methoxygonal,3,5(10),9(11)-tetraen17one treat 13,3 (3 hydroxypropyl)3methoxygona1,3,5 (l0),9-tetraen-17 onewith methanol and hydrochloric acid according to the manipu lativeprocedure described above.

To prepare 13-ethyl-3ethoxygona-1,3,5(10),9(11) tetraen-17-one treat13-ethyl3-ethoxygona1,3,5(10),8 tetraen-17-one with methanol andhydrochloric acid according to the manipulative procedure describedabove.

To prepare l3-phenethyl-3propoxygona-1,3,5 (l0),9 (11)-tetraen-17-onetreat 13-phenethy13 propoxygona- 1,3,5(l0),8tetraen17one with methanoland hydrochloric acid according to the manipulative procedure describedabove.

Example 59.-13-ethyl-3-hydroxygona-1,3,5( l0) ,9 1 l) tetraen17-oneDissolve 4-(Z-m-hydroxyphenylethyl) 8 ethyl transhexahydroindan1,5dione(l g.) in methanol (15 cc.) and add concentrated hydrochloric acid (3cc.). Warm the mixture at 40 for 1 hour, and then cool to 0. Filter theprecipitate and wash with cold methanol. Dry the product over phosphoruspentoxide to obtain 13-ethyl3hydroxy gona l,3,5(10),9(11) tetraen 17one, M.P. 262-264; ultraviolet absorption peak at 267 mn (e 15,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 60.-13-ethyl3-hydroxygona-1,3,5(10),9(11)- tetraen-17-oneDissolve 13-ethyl-3-acetoxygona-1,3,5(10),8 tetraen- 17-one in warmmethanol (125 ml.) and treat with concentrated hydrochloric acid (25cc.). Heat the solution under rellux for 45 minutes, cool and keep at 0for l hour; then filter the solid and wash with cold methanol. Dry theproduct in vacuo to obtain13-ethyl-3-hydroxygona1,3,5(10),9(l1)-tetraen-17-one, M.P. 265;ultraviolet absorption peak at 266 mp. (e 15,400).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 61 13-ethylgona-1,3,5(10),9(l l)-tetraen 3,17/3-diol Reflux 13,3ethyl 3 hydroxygona 1,3,5(10),9(11)- tetraen17one (19.52 g.) in ethanol(400 cc.) with sodium borohydride (3.94 g.) for 2 hours. Evaporate themixture almost to dryness, add water (80 cc.) and 10 N hydrochloric acid(16 cc.) and collect the product in ether. Wash, dry and evaporate theethereal solution, evaporate to a residue and recrystallize frommethanol to obtain 13/3-ethylgona-1,3,5(10),9(1l)tetraen-3,17diol as ared solid (20.86 g.); ultraviolet absorption peaks at 265 mp. (e16,200); infrared absorption peaks at 2.92 and 3.071, no carbonylabsorption.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 62.--1 3,8-n-propyl-3-hydroxygona- 1,3 ,5 10) ,9(11)-tetraen-17-one Reflux 13npropyl3-hydroxygona-1,3,5(10),8tetraen17-one (0.36 g.) with methanol (18 cc.) and concentrated hydrochloricacid (2 cc.) for 15 minutes. To the resulting pink solution add ether(100 cc.) and water (50 cc.), separate the ether solution, wash and dry.Evaporate to a residue and recrystallize from acetone to obtain13,8-npropyl-3-hydroxygona-1,3,5(10),9(11)-tetraen-17-one as colorlesscrystals (0.17 g.), M.P. 220-225"; ultraviolet absorption peaks at 266mn (e 14,000).

, This compound has estrogenic activity, lowers the blood lipid level,and is useful as an intermediate for preparing the hormonal compounds ofthis invention.

Treat 13 -ethyl-3-hydroxygona- 1 ,3,5 10 ,9 1 1 )tetraen- 17-one (0.2g.) in methanol (20 cc.) with an excess of 'an ethereal solution ofphenyldiazomethane and allow the mixture to stand for 18 hours. Addacetic acid (3 cc.) and evaporate to dryness. Take the residue up inether, wash with sodium bicarbonate solution, dry and evaporate. Filterthe residue through a column of alumina g.) and evaporate the solvent toobtain 13ethyl3benzyl 28 oxygona-1,3,5(10),9(1 1)-tetraen-17 one;ultraviolet absorption peak at 265 my. (e 18,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 64.-13-ethyl-3-acetoxygona-1,3,5(10),9(11)- tetraen-17-oneDissolve 13-ethyl 3 hydroxygona l,3,5(10),9(1l) tetraen-17-one (2.0 g.)in pyridine (5.6 cc.) and acetic anhydride (3.3 cc.) and heat at for 1hour. Remove the solvents at low pressure and dissolve the residue in alittle benzene and lter through a short column of Florisil, eluting withbenzene-petrol (3:1). Evaporate the solvent and recrystallize theresidue from ethanol to obtain 1313- ethyl-3-acetoxygor1a1,3,5(10),9(11)-tetraen-17-one, M.P. 166.5-l67; ultraviolet absorptionpeaks at 257 my (e 18,150); infrared absorption peaks at 5.73 and5.7811.

C21H24O3, calculated: C, 77.75; H, 7.46. Pound: C, 77.49; H, 7.6%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 65 .-1 3-methyl-3 -methoxygona-l,3,5 10),9( 1 l)- tetraenl7f3-ol Treat the keto-alcohol 4-(Z-m-methoxyphenylethyl)-8- methyl-S-oxo-trans hexahydroindan 1 ol (0.25 g.) in methanol (2.5 cc.) withconcentrated hydrochloric acid (1.5 cc.) at 0, and afterwards allow thesolution to warm up to room temperature. After 30 minutes lter theprecipitate formed to obtain 13-methyl-3-methoxygona-l,3,5(10),9(11)-tetraen-l7-ol (0.065 g.), M.P. 1l4-128; ultravioletabsorption peak at 264 me (e 18,500).

This compound has estr-ogenic activity, lowers the blood lipid level,and is useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 66.-13-methyl-3 -methoxy-17, 17 -ethylenedioxygona-1,3,5(10),9(11 )tetraenes Reflux 13e-methyl 3 methoxygona 1,3,5(l0),9(1l)tetraen-17-one (0.6 g.) in benzene (60 cc.) with ethylene glycol (1 cc.)and toluene-p-sulphonic acid (0.04 g.) for 15 hours using a Dean-Starkapparatus. Work up by means of ether in the usual way to obtain theketal 13-methyl-3- methoxy 17,17 ethylenedioxygona l,3,5(l0),9(11)tetraene as a solid (0.45 g.); recrystallize it from light petroleum,M.P. 13D-132 C.

C21H26O3, calculated: C, 77.3%; H, 8.0%. Found: C, 77.2%, H, 8.05%.

To prepare13ethyl3methoxy17,17-ethylenedioxygona-1,3,5(10),9(11)-tetraen treat13ethyl3meth0xy gona1,3,5(10),9(11)tetraene-17-one with excess ethyleneglycol in benzene in the presence of a catalytic amount oftoluene-p-sulphonic acid according to the manipulative proceduredescribed above.

To prepare 13-n-propyl-3-methoxy-17,l7-ethylenedioxygona 1,3,5(10),9(11)tetraene treat 13,8 propyl 3- methoxygona1,3,5( 10) ,9 1 1 )tetraen-17-one with excess ethylene glycol in benzene in the presence of acatalytic amount of toluene-p-sulphonic acid according to themanipulative procedure described above.

To prepare 13ethyl2,3dimcthoxy17,17-ethylenedioxygona-l,3,5 (10),9(11)tetraene, treat 13,B-ethyl2,3dimethoxygona-1,3,5(10),9(11)-tetraen-17-one with excess ethylene glycolin benzene in the presence of a catalytic amount of toluene-p-sulphonicacid according to the manipulative procedure described above.

To prepare13-ethyll,3dimethoxy17,17-ethylenedioxygona1,3,5(10),9(11)tetraene treat13-ethyl-l,3di methoxygona-l,3,5(10),9(11)-tetraen-l7-one with excessethylene glycol in benzene in the presence of a catalytic amount oftoulene-p-sulphonic acid according to the manipulative proceduredescribed above.

29 gona*1,3,5(l),9(11)-tetraene treat13,8-ethyl-3ethoxygona1,3,5(10),9(11)tetraen17one with excess ethyleneglycol in benzene in the presence of a catalytic amount oftoulene-p-sulphonic acid according to the manipulative proceduredescribed above.

To prepare 13-phenethyl3-propoxy-17,l7-ethylenedioxygona-1,3,5(10),9(11)tetraene treat 13phenethyl3 propoxygona-l,3,5,( 10),9( ll)-tetraen17-one with excess ethylene glycol in benzene andtoulene-p-sulphonic acid according to the manipulative proceduredescribed above.

T prepare 13-isobutyl-3-pentyloxy-17,17ethylenedioxygona1,3,5(10),9-(1l)tetraene treat 13isobutyl3pentyloxygona-l,3,5(),9(11)tetraenl7one with excess ethylene glycol inbenzene in the presence of a catalytic amount of toluenep sulphonic acidaccording to the manipulative procedure described above.

To prepare 3 -(3-hydroxyphenyl)-3-cyclopentyloxy-17,17-ethylenedioxygona-1,3,5(10),9(11)tetraene, treat 13p?- (3yhydroxyphenyl) 3 cyclopentyloxygona-l,3,5(l0),9 (11)-tetraen-l7-onewith excess ethylene glycol in benzene in the presence of a catalyticamount of toluene-p-sul phonic acid according to the manipulativeprocedure described above.

To prepare 13;?-(3-dimethylaminopropyl)-l,3dimeth oxy 17,17ethylenedioxygona-l,3,5(10),9(11)tetraene, treat 13(S-dimethyla-minopropyl)1,3dimethoxygona 1,3,5(l0),9(11)-tetraen-l7-onewith excess ethylene glycol in benzene inthe presence of a catalyticamount of toluene-p-sulphonic acid according to the manipulativeprocedure described above.

These compounds have estrogenic activity, lower the blood lipid level,and are useful as intermediates in the preparation of the hormonalcompounds of the invention.

a little benzene and lter through a column of Florisil (200 g.) withbenzene. Evaporate the solvent to obtain the title compound (22.5 g.),M.P. 14o-147.

This compound possesses estrogenic and blood lipid lowering activity andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Example 68 .-l 3-ethyl-3 -methoxy-17a-ethynylgona-1,3,5(10),9(11)-tetraene-17-ol Add lithium acetylide (3.5 g.) in dioxane(10 cc.) ethylenediamine (l0 ce), and dimethylacetamide (20 cc.) to 1313ethyl 3-methoxygona-1,3,5(10),9(11)tetraene17- one (3.5 g.) indimethylacetamide (100 cc.) with stirring in an atmosphere of acetylene.Stir the mixture for 16 hours at room temperature, then pour overcrushed ice and extract with ether. Evaporate the washed and driedextracts to a residue and chromatograph on orex to obtain a productwhich on recrystallization from methanol-water and then from ethylacetate-hexane gives l3-ethyl-3- methoxyl7ot-ethynylgonal,3,5(10),9(11)-tetraene-17/3- ol, M.P. 11G-112;ultraviolet absorption peaks at 263 ma (e 20,400); infrared absorptionpeaks at 2.80 and 3.05ft.

To obtain l3propyl3amethoxy-l7ocethynylgonal,3,5 (10),9(11) tetraen1713-01 treat 13-propyl-3-methoxygona-1,3,5(10),9(11)-tetraen-l7-onewith excess lithium acetylide according to the manipulative proceduredescribed above.

To obtain l3,3-n-butyl-3methoxy-17a-ethynylgona-1,3,5(10),9(1l)tetraen17ol treat 13e n butyl-3methoxygona1,3,5(10),9(11)-tetraen 17 one lwith the excess lithium acetylideaccording to the manipulative procedure described above.

lide according to the manipulative procedure described above.

To obtain 1313,6-dimethyl-3-methoxy-17a-ethynylgona- 1,3,5(l0),9(ll)tetraen 17ol treat l3,6dimethyl3methoxygona-1,3,5(10),9(11)-tetraen-l7-one with excess lithium acetylideaccording to the manipulative procedure described above.

To obtain l3,7dirnethyl3-methoxy-17a-ethynylgona- 1,3,5(10),9(11)tetraen 17-ol treat 13,7dimethyl3methoxygona-1,3,5(l0),9(11)-tetraen-17-one with excess lithium acetylideaccording to the manipulative procedure described above.

To obtain 3-ethyl-2,3dimethoxyl7a-ethynylgona-1,3, 5 10) ,9( 1 1)-tetraen17ol treat 13-ethylQ-dimethoxygona-1,3,5(l0),9(11)-tetraen-l7-one with excess lithiumacetylide according to the manipulative procedure described above.

To obtain 13-phenethyl-3-propoxy-17oz-ethynylgona-l,3,5(l0),9(1l)tetraenl7-ol treat l3-phenethyl-3-propoxygona1,3,5(l0),9(ll)-tetraen-l7one with excess lithium acetylide according to themanipulative procedure described above.

To obtain l3-(3-hydroxypropyl)-3-cyclopentyl-l7aethynylgona-1,3,5(10),9(11)-tetraen-17-oltreat 13-(3- hydroxypropyl) 3 cyclopentylgona 1,3,5(l0),9(11)tetraen-17-one with excess lithium acetylide according to themanipulative procedure describe above.

To obtain 13-(2-diethylaminoethyl) 2,3dimethoxyl7aethynylgona-l,3,5(l0),9(11)-tetraen-17-ol treat 13-(Z-diethylaminoethyl) 2,3 dimethoxygona1,3,5(10),9 (11)-tetraen-17-onewith excess lithium acetylide according to the manipulative proceduredescribed above.

These compounds have estrogenic activity, lower the blood lipid level,and are useful as intermediates in the preparation of the hormonalcompounds of this invention.

Treat 13,8 ethyl 3methoxygona-1,3,5(10),9(11)tet raen-l7-ol (0.5 g.) inmethylene chloride (25 cc.) containing 1 drop of boron triuorideetherate with a solution of diazomethane (from 1 g. ofN-nitrosomethylurea) in methylene chloride (20 cc.). Stir the mixturefor tive minutes, filter and wash and dry the filtrate. Remove thesolvent and recrystallize the residue trom methanol to obtain 13oethyl-3,17-dimethoxygona-l,3,5(10),9(11)- tetraene; no infraredabsorption due to hydroxyl; ultraviolet absorption peak at 266 mp. (e15,200).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

Add 13,3 ethyl 3 methoxy 17a ethynylgona-1,3, 5(10),9(11)-tetraen-17-o1(1 g.) in benzene (15 cc.) to 2% prereduced palladium on calciumcarbonate catalyst (300 mg.) in benzene (l0 cc.) and shake the mixturein an atmosphere of hydrogen until 2 molecular equivalents of hydrogencc.) has been adsorbed. Filter the catalyst and evaporate the solvent toobtain 13,17adi ethyl-B-methoxygona-1,3,5 (10),9(l1)tetraen17ol andrecrystallize from methanol, M P. 112-117; ultraviolet absorption peakat 265 mp. (e 16,100).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate for preparing the hormonal compounds ofthis invention.

To obtain 13,8 propyl 3 methoxy 17a ethylgona- 1,3,5(10),9(11) tetraen17 ol hydrogenate 13;.8 propyl 3 methoxy 17a ethynylgona 1,3,5 (10),9(11)-tetraen-17-ol according to the manipulative procedure describedabove.

tetraen-17-ol according to the manipulative procedure descri-bed above.

To obtain 1313 cetyl 3 methoxy 17a ethylgona- 1,3,5(10),9(11) tetraen 17ol hydrogenate 131icetyl 3 methoxy 17a ethylgona 1,3,5(10),9(11)tetraen-l7-ol according to the manipulative procedure described above.

To obtain 6,1313 dimethyl 3 methoxy 17a ethylgona 1,3,5(10),9(11)tetraen 1713 ol hydrogenate 6,1318 dimethyl 3 methoxy 17a ethynylgona1,3, 5(10),9(11)tetraen17ol according to the manipulative proceduredescribed above.

To obtain 7,1318 dimethyl 3 methoxy 17a ethylgona 1,3,5(10),9(11)tetraen 17,8 ol hydrogenate 7,1313 dimethyl 3 methoxy 17aethynylgona-1,3,5 (10),9(11)-tetraen-1718-ol according to themanipulative procedure described above.

To obtain 1316 ethyl 2,3 dimethoxy 17a ethylgona 1,3,5(10),9(11)tetraene 1719 o1 hydrogenate 13a ethyl 2,3 dimethoxy 17a ethynylgona1,3,5 (10),9(l1)-tetraen-l718-ol according to the manipulative proceduredescribed above.

To obtain 13111701 diethyl 3 ethoxygona 1,3,5, (l),9(1l) tetraen 1716 olhydrogenate 13p ethyl- 3 ethoxy 17a ethynylgona 1,3,5(l0),9(1l) tetraen-1713-01 according to the manipulative procedure described above.

To obtain 1313 phenethyl 3 propoxy 17a ethylgona 1,3,5(10),9(11) tetraen17p ol hydrogenate 13,6 phenethyl 3 propoxy 17m ethynylgona 1,3,5(l0),9(11)-tetraen-17-ol according to the manipulative proceduredescribed above.

To obtain 13 (3 hydroxypropyl) 3 cyclopentyloxy 17a ethylgona1,3,5(10),9(l1) tetraen 17pol hydrogenate 13,8 (3 hydroxypropyl) 3cyclopentyloxy 17a ethynylgona 1,3,5(l0),9(11) tetraen- 1718-01according to the manipulative procedure described above.

To obtain 1313 (2 diethylaminoethyl) 2,3 dimethoxy 17a ethylgona1,3,5(10),9(11) tetraen 17- ol hydrogenate 13 (2 diethylaminoethyl) 2,3dimethoxy 17u ethynylgona l,3,5(10),9(11) tetraen- 17ol according to themanipulative procedure described above.

These compounds have estrogenic activity, lower the blood lipid level,and are useful as intermediates in the preparation of the hormonalcompounds of the invention.

Example 71.-13,8-methyl-3-methoxy-D-homogona-1,3,5(10),8tetraen-17ot-one Add 1313 methyl 3 methoxy D homogona 1,3,5(l0),8,l4-pentaen17one (11 g.) in tetrahydrofuran (200 cc.) to asuspension of prereduced 2% palladized calcium carbonate (6 1g.) intetrahydrofuran (100 cc.) and shake the mixture in an atmosphere ofhydrogen until one molecular equivalent of hydrogen (896 cc.) has beenabsorbed (about 3 minutes). Filter the catalyst, remove the solvent andrecrystallize the residue from ethyl acetateethanol to obtain the titlecompound (0.5 g.), M.P. 119- 124; ultraviolet absorption peak at 27'8m11 (e 15,620).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

Example 72.--13-methyl-3-methoxygona- 1,3,5 ,8-tetraen-l7-one Dissolve1313 methyl 3 methoxygona 1,3,5(10),8, 14-pentaen-17-one (2 g.) inbenzene (60 cc.) and shake with pre-reduced 2% palladized calciumcarbonate (1 g.) in an atmosphere of hydrogen until one molecularequivalent of hydrogen has been absorbed. Filter the catalyst, evaporatethe solvent and recrystallize the residue from methanol to obtain thetitle compound (1.4 g.), M.P. 11S-119; ultraviolet absorption maximum at278 m11 (e 15,000).

32 ClgHgzO-z, calculated: C, 80.18%; H, 7.85%. Found: C, 80.5%; H, 7.9%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

Shake l3 ethyl 3 methoxygona 1,3,5(10),8,14 pentaen-l7-one (6170 g.) inbenzene (2.15 1.) with prereduced 2% palladized charcoal (225 g.) in anatmosphere of hydrogen at 25 until 57.64 l. of hydrogen have beenabsorbed (112 min.). Filter the catalyst, evaporate the solvent andrecrystallize from methanol to obtain the title compound (561.1 g.),M.P. 11G-119; ultraviolet absorption maximum at 278 m11 (e 14,600).Recrystallize further from methanol to obtain material, M.P. 122.5

C20H24O2, calculated: C, 81.0%; H, 8.1%. Found: C, 81.2%; H, 8.0%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

Add 1319 ethyl 17aa ethynyl 3 methoxy D-homogona-1,3,5(10),8tetraen17a18ol (16.2 g.) in benzene cc.) topre-reduced 2% palladized charcoal (5 g.) in benzene (150 cc.) and shakethe mixture in an atmosphere of hydrogen until one molecular equivalentof hydrogen (2,308 cc.) has been absorbed (1 hour). Filter the catalyst,evaporate the solvent and boil the residue with methanol (200 cc.). Cooland lter to obtain the title compound (13.0 g.), M.P. 16S-170;ultraviolet absorption peak at 278 ma (e 17,024).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate n the preparation of the hormonal compoundsof this invention.

Example 75 .-1318-ethyl-3-methoxy-17-methyl-D-homogona-1,3,5(10),8tetraen17a-o1 Dissolve 13,8 ethyl 3 methoxy Dhomogona 1,3, 5(10),8tetraen17aone (13.3 g.) in dry benzene (350 ce.)and add 3 molar methyl magnesium bromide in ether (200 cc.). Reflux for8 hours, cool, and add saturated aqueous ammonium chloride dropwise.Separate the organic layer, Wash, dry and evaporate and recrystallizethe residue from methanol to obtain the title product (9.2 g.), M.P.117-123; ultraviolet absorption peak at 276 my. (e 15,500).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation 'of the hormonalcompounds of this invention.

Keep l3-ethyl 3 methoxygona-1,3,5(10),8,14pen taen-l7-one (1 g.) inethanol (4 cc.), triethylorthoformate (1 cc.) and concentrated sulphuricacid (1 drop) at 45 for 30 minutes. Add triethylorthoforrnate (0.5 cc.)and keep the mixture at 55 for a further 30 minutes. Pour the cooledsolution into saturated aqueous sodium bicarbonate and extract withether. Wash, dry Vand evaporate the ethereal solution and filter theresidue through Florisil with hexane-benzene (9:1). Evaporate the eluateand recrystallize the residue from ethanol to obtain 17-ethoxy-1318-ethyl 3 methoxygona-l,3,5(l0),8,l4,l6 hexaene (0.42 g.),M.P. 79-81".

Dissolve 17 ethoxy 1313 ethyl-3-methoxygona-1,3,5 (10),8,14,16hexaene(0.25 g.) in benzene (l5 cc.) and shake with 10% palladized charcoal(0.1 g.) in an atmosphere of hydrogen at 25 until two equivalents ofhydrogen (35 cc.) have been absorbed. Filter the catalyst, evaporate thesolvent and lilter through a column of Florisil (10 g.) withbenzene-hexane (1:9). Evaporate the eluate and recrystallize the residuefrom methanol and then from acetone-methanol to obtain the titlecompound, M.P. 76-79.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

Example 77.--3-methoxy-l3methylgona1,3,5 10 ,8-tetraen-17-ol,hemisuccinate Reflux 3-methoxy-l 3rnethylgona 1 ,3,5 10) ,8-tetraen-17-ol (44 g.) in pyridine (600 cc.) with succinic anhydride (44 g.) for5 hours and then stir the solution in an atmosphere of nitrogen for 16hours. Pour the cooled solution into excess dilute hydrochloric acid andextract the mixture with chloroform. Wash, dry and evaporate thechloroform solution and triturate the residue with ether to obtain thetitle compound (41.8 g.), M.P. 145- 148.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

8-tetraen-17-ol, hemisuccinate Reflux l3ethyl-S-methoxygona-1,3,5(10),8tetraen 17,5-01 (45 g.) in pyridine (600cc.) with succinic anhydride (45 g.) for 16 hours. Pour the cooledsolution into a mixture of ice (750 g.), water (750 cc.) and 10 Nhydrochloric acid (750 cc.) and extract with chloroform. Wash, dry andevaporate the chloroform solution. Tritu rate the residue with ether anddry to obtain the title compound (51.2 g.), M.P. 164-165; ultravioletabsorption peak at 280 ma (e 16,080); infrared absorption peaks at 3.45,5.75, 5.85, 6.22,:t.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

`blood lipid level, and is useful as an intermediate in the preparationof the hormonal compounds of this invention.

Reflux 13,8 ethyl-3-methoxygona1,3,5(10),8,14pen taen-17-one (0.5 g.) inisopropenyl acetate (9 cc.) with p-toluenesulfonic acid (0.1 g.) for 15hours, and then distill off cc. of the solvent over 30 minutes. Dilutethe cooled solution with ether, wash, dry and evaporate the etherealsolution and recrystallize the residue from ethanol to obtain17-acetoxy-l3-ethyl3-methoxygona 1,3,5(l0),8,14,16hexaene (0.27 g.),M.P. 133-135".

Dissolve 17-acetoxy 13 ethyl-3-methoxygona-1,3,5 (),8,14,16hexaene (0.25g.) in benzene (25 cc.) and shake with pre-hydrogenated 10% palladizedcharcoal (0.1 g.) in an atmosphere of hydrogen until two molecularequivalents of hydrogen (35 cc.) have been absorbed. Filter thecatalyst, evaporate the solvent and filter the residue through a columnof Florisil (10 g.)

with benzene-hexane (1:1). Evaporate the eluate and recrystallize theresidue from ether-methanol to obtain the title compound, M.P. 123-126.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

Dissolve 3 acetoxy-l3ethylgona-1,3,5(10),8tetraen 17-one (0.9 g.) in asolution of sodium borohydride (0.5 g.) in ethanol cc.), keep themixture at 25 for 16 hours and then pour into ice-water and collect theprecipitate. Recrystallize from aqueous ethanol to obtain the titlecompound as a hemihydrate (0.6 g.), M.P. 182; ultraviolet absorptionpeak at 276.5 m/.t (e 15,000).

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

Example 82.-17,8-bromoacetoxy-13-methyl3 methoxygona1,3,5( 10),tl-tetraene Treat 1313 methyl-3-methoxygona-1,3,5 l0),8tetraen 17-ol(0.728 g.) in pyridine (0.4 cc.) and benzene (4 cc.) with bromoacetylbromide (0.685 g.), Allow to stand for 16 hours at 25, then add waterand extract with ether. Wash, dry and evaporate the ethereal solu tion,lter the residue through neutral alumina with benzene, and recrystallizefrom ether-hexane to obtain the title product (0.45 g.), M.P. l04-l07;ultraviolet absorption peak at 280 mp. (e 15,200).

C21H25O3Br, calculated: C, 62.22%; H, 6.21%; 19.72%. Found: C, 62.43%;H, 5.84%; Br, 19.7%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as intermediate in the preparation of the hormonal compoundsof this invention.

Reflux 6-(m-methoxyphenyl)hept-l-ene-S-one (l0 g.) withZamethylycylopentane-1,3-dione (7 g.) in 0.12% methanolic potassiumhydroxide (50 cc.) for 16 hours. Add water to the cooled mixture andisolate the product with ether to give 2(6-mmethoxyphenyl 3 oxoheptyl) 2methylcyclopentane 1,3 dione (13 g.), Reflux this Michael condensatewith anhydrous p-toluenesulfonic acid (4 g.)'in benzene (50 cc.) for 15minutes with continuous removal of water. Wash, dry and evaporate thecooled reaction mixture and distil the resulting gum at 200220 (lbathtcmp.)/0.'1 mm./Hg to obtain a pink glass. Triturate with methanol andfilter the crystals formed, M.P. 80-95. Recrystallize twice frommethanol to obtain 3-methoxy6,l7-dimethylgona-1,L,5(10),8,14`pentaen-17-one (2.5 g.), M.P. lOl-104 ultraviolet absorption peak at 314ma (e 27,800). Take up the residue from the mother liquors of the iirstrecrystallization in z little methanol and allow to stand, and filteroff the deposited crystals to obtain .3l-metho-xy-6a,17-dimethoxy`gonal,3,5(l0),8,14pentaen17one (0.04 g.), M.P. 100- 103", whichdepresses on admixture with the rst epimer Shake 6,13 dirnethoxy3methoxygona1,3,5(10), 8,14-penaten-l7-one (0.5 g.) in benzene (12 cc.)witl pre-reduced 2% palladized calcium carbonate (0.17 gQ in anatmosphere of hydrogen until one molecular equi valent of hydrogen (40cc.) has been absorbed. Filte4 the catalyst, evaporate the solvent andrecrystallize thi reisdue from methanol to give the title product (0.3g.) M.P. 88-91; ultraviolet absorption peak at 281 m, (e 15,800).

C20H24O2, Calculated: C, H, 8.2%. Found C, 80.75%; H, 8.3%.

This compound has estrogenic activity, lowers th Suspend 6/3,13-dimethyl-3-methoxygona-1,3,5( 10) ,8- tetraen-l7-one (3.0 g.) inmethanol (50 cc.) and add sodium borohydride (ca. 0.5 g.). After 30minutes add acetic acid (5 cc.) and concentrate under reduced pressureuntil crystallization commences, then add water and extract with ether.Wash and dry the organic solution, and evaporate and recrystallize theresidue from acetonitrile to obtain the title compound (2.45 g.), M P.130- 132; ultraviolet absorption peak at 280 mp. (e 15,500).

. CZOHZGOZ, calculated: C, 80.49%; H, 8.78%. Found: C, 80.41%; H, 8.65%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

Example 85 .-3-methoxy-6a,13-dimethylgona- 1,3,5( 10) ,8-tetraen17oneShake 6a,l3-dimethyl-3-methoxygona-1,3,S(10),8,14 pentaen-17-one (0.2g.) in benzene (10 cc.) with 2% palladized calcium carbonate (0.07 g.)in an atmosphere of hydrogen until enough hydrogen to saturate oneethylenic bond has been absorbed (16.5 cc.). Filter the catalyst andevaporate the solvent to obtain the title compound (0.2 g.) as anuncrystallizable gum.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

Example 86,-3-.methoxy-6a,13-dimethylgona- 1,3,5( l) ,8-tetraen-17-olAdd sodium borohydride (0.07 g.) to3-methoxya,13dimethylgona1,3,5(l0),8tetraenl7one (0.2 g.) n methanol (20cc.) and stir for 1 hour. Acidify with iqueo'us acetic acid, add waterand extract with ether. Nash, dry and evaporate the etheral solution toobtain `he crude title compound as a crystalline solid.

This compound has estrogenic activity, lowers the blood .ipid level, andis useful as an intermediate in the )reparation of the hormonalcompounds of this invention.

Example 87 .-13,I3-ethyl-3-methoxy-6-methylgona 1,3,5 l0),8-tetraen-l7-one Reflux 2 (6 rn-methoxyphenyl)-3-oxoheptyl-2-ethyl-:yclopentane-l-dione (53.3 g.) in benzene (600 cc.) Vithp-toluenesulfonic acid monohydrate (l5 g.) fOr l iou'r, using a waterseparator. Wash, dry and evaporate he benzene solution and distil theresidual gum t 0.003 mm./180200 to obtain 3-methoxy-6-methyl- 3ethylgona1,3,5(10),8,l4pentaen17one as an orange um (38.0 g.); ultravioletabsorption peak at 311 mp. e 27,200).

Shake this product (29 g.) in benzene (500 cc.) in an tmosphere ofhydrogen with 2% palladized charcoal 7 g.), Uptake of hydrogen willpractically cease when the uantity for saturation of one ethylenic bondhas been bsorbed. Filter the catalyst and evaporate the solvent a obtainthe title compound (29 g.) as a gum.

This compound has estrogenic activity, lowers the blood pid level, andis useful as an intermediate in the preparaon of the hormonal compoundsof this invention.

Add sodium borohydride (7 g.) to 13-ethyl-3methoxy methylgona1,3,5(10),8 tetraen-17-one (29 g.) in :hanol (300 cc.) and reux themixture for l hour. Add ater to the cooled reaction mixture, isolate theproduct ith ether and evaporate to obtain the title compound l2 g.) as agum.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

Example 89.-13-ethyl17(3,5-dinitrobenzoyloxy)-3-methoxy-6-methylgona-1,3 ,5 l0 ,8-tetraene Dissolve13-ethyl3-methoxy--methylgona-1,3,5(10),- 8-tetraen-l7-ol (10 g.) inpyridine (50 cc.) and add 3,5- dinitrobenzoyl chloride (8 g.). Heat themixture at 80 for 1 hour, cool and pour into dilute hydrochloric acid.Extract the mixture with ether-benzene and wash, dry and evaporate theethereal solution. Recrystallze the residue several times from ethylacetate to obtain the title compound, M.P. 20G-205.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the hormonalcompounds of this invention.

Add 6,7-dimethoxy-l-tetralone (6.1 g.) in tetrahydrofuran (50 cc.) to asolution of vinyl magnesium chloride (from magnesium 9.6 g. and excessvinyl chloride) in tetrahydrofuran (400 cc.) at 25 and stir the mixturefor 4 hours, and then pour into saturated aqueous ammonium chloride andextract with ether. Wash, dry and evaporate the ethereal solution andtake up the residue of 1,2,3,4tetrahydro-,7-dimethoxy-l-vinyl-l-tetralol in methanol (30 cc.) and addit to 2-methycyclopentane-1,3-dione (4g.) in 0.12% methanolic potassiumhydroxide (10 cc.) and rellux the mixture for 3 hours. Pour the cooledsolution onto ice, extract with ether and wash, dry and evaporate theorganic solution. Crystallize the residue from methanol to obtain2,3-dimethoxy-13methyl8,14 secogona-1,3,5(l0),9(11)tetraenel4,17dione(5.4 g.), M.P.104106.

CZHMO.,7 calculated: C, 73.12%; H, 7.37%. Found: C, 73,37%; H, 7.14%.

Add 10 N hydrochloric acid (100 cc.) to a reuxing solution of2,3-dimethoxy-13-methyl-8,14-secogona-1,3,5(l0),9(l1)-tetraene-l4,l7dione (60 g.) in methanol (600 cc.) andtetrahydrofuran (50 cc.). Cool the solution to 5, filter the precipitateand recrystallize from methanol-tetrahydrofuran to obtain2,3-dimethoxy-l3- methylgona-l,3,5(10),8,l4pentaenl7one (34 g.), MP.134-137. Purify from ethanol to obtain material, M.P. 137-140.

C20H22O3, calculated: C, 77.39%; H, 7.11%. Found: C, 77.17%; H, 7.05%.

Add 2,3 dimethoxy 13,8 methylgona 1,3,5(10), 8,14-pentaen-l7-one (2 g.)in benzene (50 cc.) to prereduced 2% palladized calcium carbonate (0.5g.) in -benzene (5 cc.) and shake the mixture in an atmosphere ofhydrogen until one molecular equivalent of hydrogen (156 cc.) has beenabsorbed. Filter the catalyst, remove the solvent and recrystallize theresidue from methanol to obtain the title compound (1.1 g.), M.P.158-162".

CZOHMOS calculated: C, 76.89%; C, 7.74%. Found: C, 76.58%; H, 7.68%.

This compound has estrogenic activity, lowers the blood lipid level, andis useful as an intermediate in the preparation of the horm-onalcompounds of this invention.

Add sodium borohydride (10 g.) to 2,3-dimethoxy-13- methylgona-1,3,5(10),8tetraen17one (10 g.) in ethanol (250 cc.) and stir the mixture for2 hours. Pour the mixture into brine and extract with ether. Wash, dryand evaporate the ethereal solution to obtain the crude title product 10g.). Recrystallize from methanol to obtain the pure compound, M.P.178-1'81".

C20H26O3, calculated: C, 76.4%; H, 8.34%. Found: C, 76.2%; H, 8.13%.

This compound has estrogenic activity, lowers the `blood

